Submissions for variant NM_007294.3(BRCA1):c.5326C>T (p.Pro1776Ser) (rs1800757)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000477350	SCV000549292	uncertain significance	Hereditary breast and ovarian cancer syndrome	2018-05-16	criteria provided, single submitter	clinical testing	This sequence change replaces proline with serine at codon 1776 of the BRCA1 protein (p.Pro1776Ser). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and serine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with ovarian cancer (PMID: 15172985, 10196379). ClinVar contains an entry for this variant (Variation ID: 409312). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
GeneDx	RCV000480229	SCV000565865	uncertain significance	not provided	2016-08-03	criteria provided, single submitter	clinical testing	This variant is denoted BRCA1 c.5326C>T at the cDNA level, p.Pro1776Ser (P1776S) at the protein level, and results in the change of a Proline to a Serine (CCC>TCC). Also reported as BRCA1 5445C>T using alternate nomenclature, this variant was observed in an individual with ovarian cancer and no family history of cancer (Janezic 1999). BRCA1 Pro1776Ser was not observed at a significant allele frequency in the NHLBI Exome Sequencing Project. Since Proline and Serine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA1 Pro1776Ser occurs at a position that is not conserved and is located within the BRCT2 domain and a region known to interact with multiple proteins (Paul 2014, UniProt). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether BRCA1 Pro1776Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.