ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.2735A>G (p.Lys912Arg) (rs397507204)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131972 SCV000187030 likely benign Hereditary cancer-predisposing syndrome 2016-02-19 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Other data supporting benign classification
GeneDx RCV000159877 SCV000209945 likely benign not specified 2017-03-26 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.
Invitae RCV000458469 SCV000549295 uncertain significance Hereditary breast and ovarian cancer syndrome 2017-10-02 criteria provided, single submitter clinical testing This sequence change replaces lysine with arginine at codon 912 of the BRCA1 protein (p.Lys912Arg). The lysine residue is moderately conserved and there is a small physicochemical difference between lysine and arginine. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with BRCA1-related disease. ClinVar contains an entry for this variant (Variation ID: 37487). 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.
Color RCV000131972 SCV000688399 likely benign Hereditary cancer-predisposing syndrome 2017-07-17 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000588317 SCV000698976 uncertain significance not provided 2017-03-24 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.2735A>G (p.Lys912Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. 4/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). Lys912 is not highly conserved across species and is not located in a known functional domain of the BRCA1 protein. The variant of interest has been found in a large, broad control population, ExAC, in 4/121364 control chromosomes, predominantly observed in the Latino subpopulation at a frequency of 0.000346 (4/11560). These frequencies are less than the estimated maximal expected allele frequency of a pathogenic BRCA1 variant (0.0010005). However, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely benign/benign without evidence for independent review. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.
Sharing Clinical Reports Project (SCRP) RCV000031068 SCV000053664 benign Breast-ovarian cancer, familial 1 2011-11-04 no assertion criteria provided clinical testing

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