Submissions for variant NM_007294.4(BRCA1):c.5444G>C (p.Trp1815Ser)

dbSNP: rs80356962

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000686696	SCV000814225	uncertain significance	Hereditary breast ovarian cancer syndrome	2022-08-08	criteria provided, single submitter	clinical testing	This sequence change replaces tryptophan, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 1815 of the BRCA1 protein (p.Trp1815Ser). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with BRCA1-related conditions. ClinVar contains an entry for this variant (Variation ID: 566786). Advanced modeling of experimental studies (such as gene expression, population dynamics, functional pathways, and cell-cycle effects in cell culture) performed at Invitae indicates that this missense variant is expected to disrupt BRCA1 protein function. Experimental studies have shown that this missense change affects BRCA1 function (PMID: 30209399). 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 Diagnostics, LLC DBA Color Health	RCV000774666	SCV000908545	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-01	criteria provided, single submitter	clinical testing	This missense variant replaces tryptophan with serine at codon 1815 of the BRCA1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). This variant has been reported to result in the loss of BRCA1 protein function in a haploid cell proliferation assay (PMID: 30209399). To our knowledge, this variant has not been reported in individuals affected with BRCA1-related disorders in the literature. This variant has been identified in 1/251486 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV000774666	SCV001186076	uncertain significance	Hereditary cancer-predisposing syndrome	2018-03-29	criteria provided, single submitter	clinical testing	The p.W1815S variant (also known as c.5444G>C), located in coding exon 21 of the BRCA1 gene, results from a G to C substitution at nucleotide position 5444. The tryptophan at codon 1815 is replaced by serine, an amino acid with highly dissimilar properties. One functional study found that this nucleotide substitution is non-functional in a high-throughput, genome editing, haploid cell survival assay (Findlay GM et al. Nature, 2018 10;562:217-222). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002469257	SCV002766352	uncertain significance	not specified	2022-11-25	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.5444G>C (p.Trp1815Ser) results in a non-conservative amino acid change located in the breast cancer carboxy-terminal (BRCT) domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251486 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.5444G>C in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome has been reported. At least one publication reports experimental evidence evaluating an impact on protein function suggesting the variant may lead to loss of protein function, however, does not allow convincing conclusions to be made about the variant effect (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. Based on the evidence outlined above, the variant was classified as uncertain significance.
Brotman Baty Institute, University of Washington	RCV001077411	SCV001243338	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro