Submissions for variant NM_007294.4(BRCA1):c.5326C>T (p.Pro1776Ser)

dbSNP: rs1800757

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000477350	SCV000549292	uncertain significance	Hereditary breast ovarian cancer syndrome	2022-04-28	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1776 of the BRCA1 protein (p.Pro1776Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with ovarian cancer (PMID: 10196379, 15172985). ClinVar contains an entry for this variant (Variation ID: 409312). 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 not expected to disrupt BRCA1 protein function. Experimental studies have shown that this missense change does not substantially affect BRCA1 function (PMID: 30209399, 30458859). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000480229	SCV004219453	uncertain significance	not provided	2023-03-02	criteria provided, single submitter	clinical testing	It has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in an individual with ovarian cancer (PMID: 10196379 (1999)). Published functional studies found that this variant is not damaging to protein function (PMIDs: 30209399 (2018) and 30458859 (2018)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Brotman Baty Institute, University of Washington	RCV001072701	SCV001238132	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro