ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.1005C>A (p.Ser335Arg) (rs876660367)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000221259 SCV000277742 uncertain significance Hereditary cancer-predisposing syndrome 2016-10-13 criteria provided, single submitter clinical testing Insufficient evidence;In silico models in agreement (benign)
Invitae RCV000475154 SCV000549394 uncertain significance Hereditary breast and ovarian cancer syndrome 2016-04-29 criteria provided, single submitter clinical testing This sequence change replaces serine with arginine at codon 335 of the BRCA1 protein (p.Ser335Arg). The serine residue is moderately conserved and there is a moderate physicochemical difference between serine and arginine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a BRCA1-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. A different variant c.1124C>G giving rise to the same protein effect observed here (p.Ser335Arg) has been reported in a patient affected with ovarian cancer (PMID: 11733976), indicating that this residue may be critical for protein function. In summary, this variant is a rare missense change that is not predicted to affect protein function. While it is absent from the population and a variant that gives rise to the same protein effect has been reported in an affected individual, the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Integrated Genetics/Laboratory Corporation of America RCV000589343 SCV000698825 uncertain significance not provided 2017-02-21 criteria provided, single submitter clinical testing Variant summary: The BRCA1 1005C>A (p.Ser335Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. 3/3 in silico tools predict a benign outcome for this variant. (SNPs&GO not captured due to low reliability index). This variant is absent in 121404 control chromosomes. Ambry Genetics classified this variant as uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications; 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.
Color RCV000221259 SCV001341302 uncertain significance Hereditary cancer-predisposing syndrome 2019-08-06 criteria provided, single submitter clinical testing

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