ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.4882A>G (p.Met1628Val) (rs80357465)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130592 SCV000185465 likely benign Hereditary cancer-predisposing syndrome 2018-06-18 criteria provided, single submitter clinical testing In silico models in agreement (benign);Intact protein function observed in appropriate functional assay(s)
CSER _CC_NCGL, University of Washington RCV000148406 SCV000190105 uncertain significance Breast neoplasm 2014-06-01 criteria provided, single submitter research Low GERP score may suggest that this variant may belong in a lower pathogenicity class
GeneDx RCV000212187 SCV000209979 likely benign not specified 2017-03-01 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. RCV000130592 SCV000747798 likely benign Hereditary cancer-predisposing syndrome 2018-01-16 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000761958 SCV000892185 uncertain significance not provided 2018-06-01 criteria provided, single submitter clinical testing
Color Health, Inc RCV000130592 SCV000910925 likely benign Hereditary cancer-predisposing syndrome 2015-01-17 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000212187 SCV000916723 benign not specified 2021-06-13 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.4882A>G (p.Met1628Val) 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 2e-05 in 251478 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4882A>G has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer (example, Durocher_1996, Troudi_2007, Lu_2012). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Co-occurrences with other pathogenic variant(s) have been observed in the UMD database and at our laboratory (UMD database-BRCA1 c.25G>T, p.Glu9*; our laboratory-BRCA1 c.4357+1G>A), providing supporting evidence for a benign role. Multiple publications report contradictory experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in a loss of transcriptional activation similar to a null allele (Phelan_2005), whereas another study evaluating transcriptional acitivity reported a neutral outcome (Frenandes_2019). Another assay measuring yeast colony size found no difference when compared to a WT control (Coyne_2004). Other reports have classified the variant as a VUS (Iversen_2011), as likely not pathogenic (Woods_2016) based on functional studies.. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and a predominant consensus leaning towards likely benign (n=6)/benign (n=1) and one submitter reporting a VUS outcome. Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as benign.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000761958 SCV001133597 likely benign not provided 2019-04-24 criteria provided, single submitter clinical testing
Mendelics RCV000112414 SCV001140507 benign Breast-ovarian cancer, familial 1 2019-05-28 criteria provided, single submitter clinical testing
Invitae RCV001474576 SCV001678747 likely benign Hereditary breast and ovarian cancer syndrome 2020-11-13 criteria provided, single submitter clinical testing
Research and Development, ARUP Laboratories RCV001663951 SCV001878394 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
Breast Cancer Information Core (BIC) (BRCA1) RCV000112414 SCV000145200 uncertain significance Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353677 SCV000591544 likely benign Malignant tumor of breast no assertion criteria provided clinical testing The p.Met1628Val variant has been previously reported in the literature in 2/40128 proband chromosomes of individuals with breast cancer. However, no controls were tested to establish the frequency of the variant in the general population (Abkevich_2004_15235020, Iversen_2011_21447777, Phelan_2005_15689452, Carvalho_2007_17308087, Tamboom_2010_20380699). Functional studies have reported that the variant displayed ~80% of the wild-type activity, suggesting that it corresponds to a neutral variant (Phelan_2005_15689452, Carvalho_2007_17308087). The variant has been reported in the UMD (x3), BIC (6x with unknown clinical importance), dbSNP (ID:rs80357465) and the Exome Variant Server (frequency: 0.0002) and CNPHI (ACMG3) databases. In the UMD database, the variant was observed to co-occur with another BRCA1 pathogenic mutation: BRCA1: c.25G>T (p.Glu9X), increasing the likelihood that the p.Met1628Val variant does not have any clinical significance. This residue is not conserved in mammals and computational analyses (PolyPhen, SIFT, AlignGVGD) do not suggest a high likelihood of impact to the protein. In addition, the variant amino acid valine (Val) is present in the mouse at this position, increasing the likelihood that an alteration to this residue may not have functional significance. However, this information is not predictive enough to rule out pathogenicity. It should be noted that although this variant occurs outside of the splicing consensus sequence, in-silico or computational prediction software (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predicts a greater than 10% difference in splicing in 2 of 5 different programs. However, this information is not predictive enough to determine the clinical significance of this variant. 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. The p.Met1628Val variant is classified as predicted benign.

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