ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.305C>G (p.Ala102Gly) (rs80357190)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000031086 SCV001161499 benign Breast-ovarian cancer, familial 1 2019-06-18 reviewed by expert panel curation IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.000724
Invitae RCV000203639 SCV000076075 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-01-01 criteria provided, single submitter clinical testing This sequence change replaces alanine with glycine at codon 102 of the BRCA1 protein (p.Ala102Gly). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and glycine. This variant is not present in population databases (rs80357190, ExAC no frequency). This variant has been reported in a family with hereditary breast and ovarian cancer, as well as an unrelated individual with ovarian cancer (PMID: 18703817, 22711857). This variant was present on the same chromosome with a pathogenic BRCA1 variant in the family (PMID: 18703817). ClinVar contains an entry for this variant (Variation ID: 37505). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV000048062 SCV000209905 likely benign not specified 2017-03-31 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.
Ambry Genetics RCV000166160 SCV000216934 uncertain significance Hereditary cancer-predisposing syndrome 2014-10-02 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000048062 SCV000591258 uncertain significance not specified 2015-06-25 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000048062 SCV000699001 uncertain significance not specified 2019-01-30 criteria provided, single submitter clinical testing Variant summary: The variant, BRCA1 c.305C>G (p.Ala102Gly) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 245488 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.305C>G has been reported in the literature in individuals affected with Breast cancer and ovarian cancer ((Alsop_2012, Palma_2008)). However, these reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrences with other pathogenic variants have been reported (BRCA1 Del exons 8-9), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Based on the evidence outlined above, the variant was classified as VUS- Possibly Benign.
Color RCV000166160 SCV000903872 likely benign Hereditary cancer-predisposing syndrome 2016-04-21 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000031086 SCV000053682 likely benign Breast-ovarian cancer, familial 1 2012-07-17 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000031086 SCV000144993 uncertain significance Breast-ovarian cancer, familial 1 2004-11-25 no assertion criteria provided clinical testing

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