ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.3445A>G (p.Met1149Val) (rs80358589)

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Total submissions: 17
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000044195 SCV000072208 benign Hereditary breast and ovarian cancer syndrome 2020-12-07 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 Co-occurence with mutation in same gene (phase unknown);In silico models in agreement (benign);Subpopulation frequency in support of benign classification
CSER _CC_NCGL, University of Washington RCV000148431 SCV000190130 likely benign Carcinoma of esophagus 2014-06-01 criteria provided, single submitter research
Illumina Clinical Services Laboratory,Illumina RCV000044195 SCV000383677 likely benign Hereditary breast and ovarian cancer syndrome 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000315582 SCV000383678 likely benign Fanconi anemia 2016-06-14 criteria provided, single submitter clinical testing
Color Health, Inc RCV000131758 SCV000683557 likely benign Hereditary cancer-predisposing syndrome 2015-04-24 criteria provided, single submitter clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000077303 SCV000743285 uncertain significance Breast-ovarian cancer, familial 2 2014-10-08 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000758884 SCV000887791 benign not provided 2018-08-05 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 2 2019-05-28 criteria provided, single submitter clinical testing
Research and Development, ARUP Laboratories RCV001646171 SCV001854763 likely benign Breast-ovarian cancer, familial 2; Breast-ovarian cancer, familial 1; Hereditary breast and ovarian cancer syndrome 2020-01-20 criteria provided, single submitter curation
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 2 2009-09-01 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000077303 SCV000146234 uncertain significance Breast-ovarian cancer, familial 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 and 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.

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