Submissions for variant NM_007294.4(BRCA1):c.3572G>A (p.Ser1191Asn)

gnomAD frequency: 0.00001  dbSNP: rs878854948

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000233599	SCV000289781	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-05-12	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 1191 of the BRCA1 protein (p.Ser1191Asn). 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: 240794). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA1 protein function with a negative predictive value of 95%. 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	RCV000772341	SCV000905515	uncertain significance	Hereditary cancer-predisposing syndrome	2020-06-10	criteria provided, single submitter	clinical testing	This missense variant replaces serine with asparagine at codon 1191 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 not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified 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	RCV000772341	SCV001182146	uncertain significance	Hereditary cancer-predisposing syndrome	2024-09-02	criteria provided, single submitter	clinical testing	The p.S1191N variant (also known as c.3572G>A), located in coding exon 9 of the BRCA1 gene, results from a G to A substitution at nucleotide position 3572. The serine at codon 1191 is replaced by asparagine, an amino acid with highly similar properties. This variant was identified in a cohort of 33 unrelated families from Libya with a history suggestive of hereditary breast cancer (Elmaihub ES et al. Libyan J Med, 2024 Dec;19:2356906). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000772341	SCV003848481	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).