ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.4828G>A (p.Val1610Met) (rs80358705)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000044498 SCV000072511 benign Hereditary breast and ovarian cancer syndrome 2020-12-03 criteria provided, single submitter clinical testing
GeneDx RCV001353552 SCV000108615 likely benign not provided 2020-07-29 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 18284688, 16905680, 26898890, 27495310, 25479140, 21952622, 25348012, 10923033)
Ambry Genetics RCV000130783 SCV000185676 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)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000074530 SCV000694805 benign not specified 2020-11-23 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.4828G>A (p.Val1610Met) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 9.6e-05 in 250074 control chromosomes, predominantly at a frequency of 0.00021 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in BRCA2 causing Hereditary Breast and Ovarian Cancer (9.6e-05 vs 0.00075), allowing no conclusion about variant significance. c.4828G>A has been reported in the literature in individuals affected with Breast and Ovarian Cancer (example, Lee_2008, Kote-Jarai_2011, Simard_2007, Caminsky_2016, Jarhelle_2016). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. At-least two known co-occurrences with other pathogenic variant(s) have been reported (UMD database-BRCA1 c.4327C>T, p.Arg1443*; BIC database-BRCA1 c.3481_3491delGAAGATACTAG, p.Glu1161_Ser1164?fs), providing supporting evidence for a benign role. Two recent reports from the CAGI5 (fifth Critical Assessment of Genome Interpretation) challenge have classified this variant as likely benign in a prediction protocol that includes assessment of the impact of this variant on splicing and protein function using four sets of predictors (Padilla_2019, Cline_2019). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Four have classified the variant as Benign/Likely Benign and two classified the variant as uncertain significance citing overlapping references utilized in the context of this evaluation. Based on the evidence outlined above, the variant was re-classified as benign.
Color Health, Inc RCV000130783 SCV000910745 benign Hereditary cancer-predisposing syndrome 2017-01-25 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001112023 SCV001269637 uncertain significance Fanconi anemia, complementation group D1 2017-04-28 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Clinical Services Laboratory,Illumina RCV000031508 SCV001269638 uncertain significance Breast-ovarian cancer, familial 2 2017-04-28 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Research and Development, ARUP Laboratories RCV001642349 SCV001854808 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
Sharing Clinical Reports Project (SCRP) RCV000031508 SCV000054113 benign Breast-ovarian cancer, familial 2 2009-08-31 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000031508 SCV000146488 uncertain significance Breast-ovarian cancer, familial 2 2004-02-20 no assertion criteria provided clinical testing
Department of Medical Genetics, University Hospital of North Norway RCV000031508 SCV000301448 uncertain significance Breast-ovarian cancer, familial 2 2016-05-01 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353552 SCV000591929 likely benign not provided no assertion criteria provided clinical testing The BRCA2 p.Val1610Met variant was identified in 6 of 8922 proband chromosomes (frequency: 0.0007) from individuals with hereditary breast and ovarian cancer and prostate cancer (Simard 2007, Caminsky 2016, Jarhelle 2016, Dolman 2013, Kote-Jarai 2011, Lee 2008). The variant was identified in dbSNP (rs80358705) as “with other allele”, in ClinVar (interpreted as "uncertain significance" by Sinai Health System and 3 others, "benign" Invitae and 2 others and "likely benign" by Ambry Genetics and 1 other), LOVD 3.0 (observed 2x) and UMD-LSDB (observed 3x). The variant was identified in control databases in 23 of 245,458 chromosomes at a frequency of 0.00009 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 23 of 111,150 chromosomes (freq: 0.0002), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. In the UMD-LSDB database, the variant co-occurred with a pathogenic BRCA1 variant (p.Arg1443*). Additionally, a clinical laboratory reported the variant occurred with another pathogenic BRCA1 variant (p.Glu1161fsX3). The p.Val1610 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) do not predict a difference in splicing. 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 likely benign.

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