Submissions for variant NM_000059.4(BRCA2):c.3445A>G (p.Met1149Val)

gnomAD frequency: 0.00013  dbSNP: rs80358589

Total submissions: 26

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000044195	SCV000072208	benign	Hereditary breast ovarian cancer syndrome	2024-01-28	criteria provided, single submitter	clinical testing
GeneDx	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)
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.
CSER _CC_NCGL, University of Washington	RCV000148431	SCV000190130	likely benign	Carcinoma of esophagus	2014-06-01	criteria provided, single submitter	research
Illumina Laboratory Services, Illumina	RCV000044195	SCV000383677	likely benign	Hereditary breast ovarian cancer syndrome	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000315582	SCV000383678	likely benign	Fanconi anemia	2016-06-14	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131758	SCV000683557	likely benign	Hereditary cancer-predisposing syndrome	2015-04-24	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000758884	SCV000887791	benign	not provided	2022-10-21	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	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.
Mendelics	RCV000077303	SCV001139062	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2019-05-28	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV000044195	SCV002026088	likely benign	Hereditary breast ovarian cancer syndrome	2021-11-16	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000758884	SCV002048603	likely benign	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000131758	SCV002533795	likely benign	Hereditary cancer-predisposing syndrome	2020-09-10	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000120318	SCV002761153	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Genetics and Molecular Pathology, SA 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).
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149676	SCV003838151	likely benign	Breast and/or ovarian cancer	2023-01-17	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000758884	SCV004132979	likely benign	not provided	2022-07-01	criteria provided, single submitter	clinical testing	BRCA2: BP4
All of Us Research Program, National Institutes of Health	RCV000077303	SCV004845161	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2023-12-01	criteria provided, single submitter	clinical testing
ITMI	RCV000120318	SCV000084470	not provided	not specified	2013-09-19	no assertion provided	reference population
Sharing Clinical Reports Project (SCRP)	RCV000077303	SCV000109100	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2009-09-01	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000077303	SCV000146234	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2004-02-20	no assertion criteria provided	clinical testing
Cancer Genetics and Genomics Laboratory, British Columbia Cancer Agency	RCV000044195	SCV000586942	uncertain significance	Hereditary breast ovarian cancer syndrome	2017-04-18	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	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.
Center for Precision Medicine, Meizhou People's Hospital	RCV002250510	SCV002520783	likely benign	Familial cancer of breast		no assertion criteria provided	literature only
BRCAlab, Lund University	RCV000077303	SCV004243603	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2020-03-02	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	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).