Submissions for variant NM_007294.4(BRCA1):c.3533G>A (p.Ser1178Asn)

gnomAD frequency: 0.00001  dbSNP: rs1294360179

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000510057	SCV000607825	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-17	criteria provided, single submitter	clinical testing	The p.S1178N variant (also known as c.3533G>A), located in coding exon 9 of the BRCA1 gene, results from a G to A substitution at nucleotide position 3533. The serine at codon 1178 is replaced by asparagine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV000552904	SCV000635901	likely benign	Hereditary breast ovarian cancer syndrome	2023-10-09	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001194381	SCV001363876	uncertain significance	not specified	2022-10-14	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.3533G>A (p.Ser1178Asn) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251222 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3533G>A has been reported as a variant of uncertain significance in the literature in an individual affected with colorectal cancer (Yurgelun 2017). This report does not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000510057	SCV003851679	likely benign	Hereditary cancer-predisposing syndrome	2023-03-23	criteria provided, single submitter	curation	Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
Color Diagnostics, LLC DBA Color Health	RCV000510057	SCV004360227	uncertain significance	Hereditary cancer-predisposing syndrome	2021-07-26	criteria provided, single submitter	clinical testing	This missense variant replaces serine with asparagine at codon 1178 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 reported for an individual affected with colorectal cancer (PMID: 28135145). This variant has been identified in 2/251222 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.