Total submissions: 27
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Mayo Clinic Laboratories, |
RCV000120318 | SCV007303667 | benign | not specified | 2025-02-14 | criteria provided, single submitter | clinical testing | BA1, BP1_strong, BP5_strong |
| Molecular Diagnostics Laboratory, |
RCV000131758 | SCV006324763 | benign | Hereditary cancer-predisposing syndrome | 2025-04-22 | criteria provided, single submitter | clinical testing | BS1, BP1_Strong, BP5_Strong c.3445A>G, located outside any (potentially) clinically important functional domain of BRCA2, is predicted to result in the substitution of Methionine�by Valine�at�codon�1149,�p.(Met1149Val). In addition, the SpliceAI algorithm predicts no significant impact on splicing (BP1_Strong). The variant allele was found in 24/19246 alleles, with a filter allele frequency of 0.0106% at 99% confidence, within the East Asian population in the gnomAD v2.1.1 database (non-cancer data set) (BS1). This alteration was classified as a likely benign variant in a multifactorial likelihood analysis showing a Combined LR for clinical data indicative of strong evidence towards benign (LR 0.0241), co-occurrence LR 0.0576 and family history LR 0.419 (PMID: 31131967) (BP5_Strong). It has been identified in the ClinVar (6x benign, 12x likely benign), LOVD (2x benign, 4x likely benign, 2x NA, 18x uncertain significance) and BRCA Exchange (not yet reviewed) databases. Additional information has not been evaluated for this variant. Based on the currently available information, c.3445A>G is classified as a benign variant according to ClinGen-BRCA2 Guidelines version 1. |
| All of Us Research Program, |
RCV004803160 | SCV004845161 | likely benign | BRCA2-related cancer predisposition | 2024-08-13 | criteria provided, single submitter | clinical testing | |
| Ce |
RCV000758884 | SCV004132979 | likely benign | not provided | 2022-07-01 | criteria provided, single submitter | clinical testing | BRCA2: BP4 |
| CHEO Genetics Diagnostic Laboratory, |
RCV003149676 | SCV003838151 | likely benign | Breast and/or ovarian cancer | 2023-01-17 | criteria provided, single submitter | clinical testing | |
| Genetics and Molecular Pathology, |
RCV000077303 | SCV002761572 | likely benign | Breast-ovarian cancer, familial, susceptibility to, 2 | 2020-10-14 | criteria provided, single submitter | clinical testing | The BRCA2 c.3445A>G variant is classified as Likely Benign (BP4, BP6) The BRCA2 c.3445A>G variant is a single nucleotide change in the BRCA2 gene, which is predicted to change the amino acid methionine at position 1149 in the protein to valine. Multiple lines of computational evidence suggest this variant has no impact on the gene or gene product (BP4). The variant has been reported in dbSNP (rs80358589) and has been reported as Conflicting interpretations of pathogenicity by other diagnostic laboratories (ClinVar Variation ID: 51465). |
| Center for Genomic Medicine, |
RCV000120318 | SCV002761153 | benign | not specified | 2025-03-04 | criteria provided, single submitter | clinical testing | |
| Sema4, |
RCV000131758 | SCV002533795 | likely benign | Hereditary cancer-predisposing syndrome | 2020-09-10 | criteria provided, single submitter | curation | |
| ARUP Laboratories, |
RCV000758884 | SCV002048603 | benign | not provided | 2025-03-18 | criteria provided, single submitter | clinical testing | |
| National Health Laboratory Service, |
RCV000044195 | SCV002026088 | likely benign | Hereditary breast ovarian cancer syndrome | 2021-11-16 | criteria provided, single submitter | clinical testing | |
| Mendelics | RCV000077303 | SCV001139062 | benign | Breast-ovarian cancer, familial, susceptibility to, 2 | 2019-05-28 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000120318 | SCV000916997 | benign | not specified | 2017-12-06 | criteria provided, single submitter | clinical testing | Variant summary: The BRCA2 c.3445A>G (p.Met1149Val) variant involves the alteration of a non-conserved nucleotide, not located in any known domain. 3/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 49/280622 control chromosomes, predominantly observed in the East Asian subpopulation at a frequency of 0.001219 (23/18862). This frequency is about 2 times the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503), suggesting this is likely a benign polymorphism found primarily in the populations of East Asian origin. The variant of interest have been observed in multiple affected individuals with limited information concerning co-occurrence and co-segregation data. One study reported the variant of interest in a 56 y/o individual with no cancer, who had a family history of BrC, suggesting the variant not segregate with disease (Carney_2010). A case-control study in Asian population showed that this variant does not associate with Breast Cancer (OR=0.83, P=0.74, Lai_2017). UMD reports the variant to co-occur with another potentially pathogenic BRCA2 variant, c.2092delC (Leu698Tyrfs). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign/likely benign. Taken together, this variant is classified as benign. |
| Quest Diagnostics Nichols Institute San Juan Capistrano | RCV000758884 | SCV000887791 | benign | not provided | 2022-10-21 | criteria provided, single submitter | clinical testing | |
| Color Diagnostics, |
RCV000131758 | SCV000683557 | likely benign | Hereditary cancer-predisposing syndrome | 2015-04-24 | criteria provided, single submitter | clinical testing | |
| CSER _CC_NCGL, |
RCV000148431 | SCV000190130 | likely benign | Carcinoma of esophagus | 2014-06-01 | criteria provided, single submitter | research | |
| Ambry Genetics | RCV000131758 | SCV000186801 | likely benign | Hereditary cancer-predisposing syndrome | 2018-10-31 | criteria provided, single submitter | clinical testing | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. |
| Gene |
RCV000758884 | SCV000108610 | likely benign | not provided | 2021-01-28 | criteria provided, single submitter | clinical testing | This variant is associated with the following publications: (PMID: 24055113, 24728327, 18627636, 18431501, 22126563, 22293751, 17972177, 21120943, 25637381, 27376475, 28222693, 22486713, 21523855, 27633797, 10923033, 30093976) |
| Labcorp Genetics |
RCV000044195 | SCV000072208 | benign | Hereditary breast ovarian cancer syndrome | 2026-02-04 | criteria provided, single submitter | clinical testing | |
| Dr. |
RCV002250510 | SCV006809840 | not provided | Familial cancer of breast | no classification provided | in vitro | ||
| Prevention |
RCV004537192 | SCV004739479 | likely benign | BRCA2-related disorder | 2019-03-26 | no assertion criteria provided | clinical testing | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). |
| BRCAlab, |
RCV000077303 | SCV004243603 | likely benign | Breast-ovarian cancer, familial, susceptibility to, 2 | 2020-03-02 | no assertion criteria provided | clinical testing | |
| Center for Precision Medicine, |
RCV002250510 | SCV002520783 | likely benign | Familial cancer of breast | no assertion criteria provided | literature only | ||
| Department of Pathology and Laboratory Medicine, |
RCV001353693 | SCV000591861 | likely benign | Malignant tumor of breast | no assertion criteria provided | clinical testing | The BRCA2 p.Met1149Val variant was identified in 6 of 3530 proband chromosomes (frequency: 0.002) from individuals or families with breast and ESCC cancer (Bodian 2014, Dorschner 2013, Theng Toh 2008, Zhong 2011). The variant was also identified in dbSNP (ID: rs80358589), with a minor allele frequency of 0.001 (1000 Genomes Project), NHLBI Exome Sequencing Project (Exome Variant Server), Exome Aggregation Consortium (ExAC) database, HGMD, the ClinVar database (classified as a benign variant by the Sharing Clinical Reports Project, derived from Myriad reports; classified as likely benign by Ambry Genetics; classified as uncertain significance by Invitae, GeneDX, BIC and CSER_CC_NCGL ), the BIC database (8X with unknown clinical importance), and UMD (4X as an unclassified variant). In UMD the variant was identified with a co-occurring pathogenic BRCA2 variant (c.2092delC (p.Leu698TyrfsX32)), increasing the likelihood that the p.Met1149Val variant does not have clinical significance. This variant was identified in the 1000 Genomes Project in 5 of 5000 chromosomes (frequency: 0.001), Exome Variant Server project in 4 of 4406 African American alleles, the Exome Aggregation Consortium (ExAC) database (released Oct 20th, 2014) in 26 of 18988 chromosomes (frequency: 0.001) from a population of East Asian and African individuals, increasing the likelihood that this may be a low frequency benign variant in certain populations of origin.The p.Met1149 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein. However, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. A study by Theng Toh (2008) suggested variant is predicted to be a neutral alteration that has little clinical significance and occurs at a residue that is not evolutionarily conserved. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as predicted benign. | |
| Cancer Genetics and Genomics Laboratory, |
RCV000044195 | SCV000586942 | uncertain significance | Hereditary breast ovarian cancer syndrome | 2017-04-18 | no assertion criteria provided | clinical testing | |
| Breast Cancer Information Core |
RCV000077303 | SCV000146234 | uncertain significance | Breast-ovarian cancer, familial, susceptibility to, 2 | 2004-02-20 | no assertion criteria provided | clinical testing | |
| Sharing Clinical Reports Project |
RCV000077303 | SCV000109100 | benign | Breast-ovarian cancer, familial, susceptibility to, 2 | 2009-09-01 | no assertion criteria provided | clinical testing | |
| ITMI | RCV000120318 | SCV000084470 | not provided | not specified | 2013-09-19 | no classification provided | reference population |