ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.1396C>T (p.Arg466Trp) (rs80356964)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000132353 SCV000187442 likely benign Hereditary cancer-predisposing syndrome 2017-04-19 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Genetic Services Laboratory, University of Chicago RCV000502109 SCV000593671 uncertain significance not specified 2017-03-29 criteria provided, single submitter clinical testing
Color Health, Inc RCV000132353 SCV000682958 uncertain significance Hereditary cancer-predisposing syndrome 2021-02-03 criteria provided, single submitter clinical testing This missense variant replaces arginine with tryptophan at codon 466 of the BRCA1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been detected in one unaffected individual and absent in breast and ovarian cancer cases in a small breast/ovarian cancer case-control study (PMID: 12872252 ), and it has been reported in a multifactorial analysis with a family history likelihood ratio of 0.0745 (PMID: 31131967). This variant has been identified in 4/282490 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion that this variant may not be associated with disease, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Invitae RCV001485675 SCV001690121 likely benign Hereditary breast and ovarian cancer syndrome 2020-11-25 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000030991 SCV000053583 benign Breast-ovarian cancer, familial 1 2012-05-01 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000030991 SCV000144083 uncertain significance Breast-ovarian cancer, familial 1 2004-02-20 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353504 SCV000591327 likely benign not provided no assertion criteria provided clinical testing The p.Arg466Trp variant was not identified in the literature but was identified in dbSNP (ID: rs80356964) “With other, untested allele”, UMD (1X as an unclassified variant), and the BIC database (4X with unknown clinical importance). It was classified as a benign variant by the Sharing Clinical Reports Project (SCRP) (submitted within the ClinVar database and derived from Myriad reports), increasing the likelihood this variant does not have clinical significance. The p.Arg466 residue is not conserved in mammals and lower organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. 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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