ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.5152T>G (p.Trp1718Gly) (rs1567769155)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color Health, Inc RCV000772239 SCV000905357 uncertain significance Hereditary cancer-predisposing syndrome 2019-03-14 criteria provided, single submitter clinical testing
Ambry Genetics RCV000772239 SCV001185534 uncertain significance Hereditary cancer-predisposing syndrome 2017-12-22 criteria provided, single submitter clinical testing The c.5152T>G variant (also known as p.W1718G), located in coding exon 16 of the BRCA1 gene, results from a T to G substitution at nucleotide position 5152. The amino acid change results in tryptophan to glycine at codon 1718, an amino acid with highly dissimilar properties. However, this change occurs in the last base pair of coding exon 16, which makes it likely to have some effect on normal mRNA splicing. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV001050456 SCV001214564 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-02-25 criteria provided, single submitter clinical testing This sequence change replaces tryptophan with glycine at codon 1718 of the BRCA1 protein (p.Trp1718Gly). The tryptophan residue is highly conserved and there is a large physicochemical difference between tryptophan and glycine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with BRCA1-related conditions. This variant has been reported to affect BRCA1 protein function (PMID: 30209399). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001050456 SCV001623344 likely pathogenic Hereditary breast and ovarian cancer syndrome 2021-04-18 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.5152T>G (p.Trp1718Gly) results in a non-conservative amino acid change located in the BRCT domain (IPR001357) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. BRCT domain is highly conserved and known to interact with multiple phospho-proteins in facilitating the tumor suppression function of BRCA1 (Sinha_2021). Other pathogenic variants in the BRCT domain have been reported. However, a computational study utilizing molecular dynamic simulation to classify VUS in the BRCT domain of BRCA1 reported this change as tolerated (Singh_2020). This variant also alters the last nucleotide of exon 17 adjacent to the canonical splice donor site. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251212 control chromosomes. c.5152T>G has been reported in the literature in at-least one individual affected with breast cancer in a large study that used a panel of 34 putative susceptibility genes to perform sequencing on 60,466 women with breast cancer and 53,461 controls (example, Dorling_2021). These data do not allow unequivocal conclusions about variant significance. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in a loss of HDR activity (example, Findlay_2018). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. At-least one submitter cites overlapping functional evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Brotman Baty Institute,University of Washington RCV001076083 SCV001241768 not provided Breast-ovarian cancer, familial 1 no assertion provided in vitro

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