Submissions for variant NM_007294.4(BRCA1):c.3616G>T (p.Ala1206Ser)

dbSNP: rs1555587407

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000510023	SCV000608094	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-08	criteria provided, single submitter	clinical testing	The p.A1206S variant (also known as c.3616G>T), located in coding exon 9 of the BRCA1 gene, results from a G to T substitution at nucleotide position 3616. The alanine at codon 1206 is replaced by serine, an amino acid with 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000590578	SCV000699046	uncertain significance	not provided	2016-05-02	criteria provided, single submitter	clinical testing	Variant summary: The c.3616G>T variant affects a non-conserved nucleotide, resulting in amino acid change from Ala to Ser. 4/4 in-silico tools predict benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant is not found in 120884 control chromosomes. 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. One reputable clinical lab has classified the variant as a VUS. Because of the absence of clinical information and the lack of functional studies, the variant was classified as a variant of uncertain significance (VUS) until additional information becomes available.
Invitae	RCV000701491	SCV000830294	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-05-24	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1206 of the BRCA1 protein (p.Ala1206Ser). 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: 441433). 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. 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000510023	SCV003846597	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).