Submissions for variant NM_007294.4(BRCA1):c.5327C>A (p.Pro1776His)

dbSNP: rs398122695

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000236047	SCV000293617	likely benign	not specified	2017-08-29	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics	RCV000569030	SCV000665886	likely benign	Hereditary cancer-predisposing syndrome	2021-03-23	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Invitae	RCV000695187	SCV000823670	likely benign	Hereditary breast ovarian cancer syndrome	2023-06-10	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003477845	SCV004219454	uncertain significance	not provided	2023-01-18	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 a large breast cancer association study in one individual with breast cancer (PMID: 33471991 (2021)). In one functional study, the variant was reported as functional (PMID: 30209399 (2018)), and in another study the variant behaved similar to the wild type BRCA1 protein (PMID: 27272900 (2016)). In addition, published multifactorial analyses have reported inconclusive results (PMID: 18824701 (2008), 31131967 (2019)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Color Diagnostics, LLC DBA Color Health	RCV000569030	SCV004360118	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-11	criteria provided, single submitter	clinical testing	This missense variant replaces proline with histidine at codon 1776 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have reported that this variant does not impact BRCA1 function in a haploid cell proliferation assay and transcription activation, yeast colony size, homology-directed DNA repair and cisplatin resistance assays (PMID: 27272900, 29884841, 30209399, 35196514). This variant has been reported in at least two individuals affected with breast cancer (PMID: 18824701, 32885271) and it has been detected in a breast cancer case-control meta-analysis in 1/60466 cases and 0/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_000454). Multifactorial analyses using tumor pathology, functional studies and family history have reported this variant to be likely not associated with disease (PMID: 18824701, 21990134, 33087888). 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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353630	SCV000591613	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA1 p.Pro1776His variant has been previously reported in the literature in several studies that use in silico models to assess the clinical significance of the variant (Lindor 2011, Rajasekaran 2007, Williams 2003), however, these studies had conflicting results and this information was not very predictive of pathogenicity. The variant was also identified in dbSNP (ID: rs398122695) as "With Uncertain significance, other allele ", in ClinVar (classified as likely benign by GeneDx; as uncertain significance by Ambry Genetics), LOVD 3.0, and ARUP Laboratories (likely not pathogenic or of little clinical significance). The variant was not identified in Cosmic, MutDB, UMD-LSDB, BIC Database, and Zhejiang University databases. The variant was identified in control databases in 1 of 246152 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in African population in 1 of 15280 chromosomes (freq: 0.00007), while the variant was not observed in the Ashkenazi Jewish, East Asian, Finnish, European, Latino, Other, and South Asian populations. The p.Pro1776 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 3 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume pathogenicity. In addition, the functional assessment of genetic variants by Thouvenot (2016) in a colony size assay identified the probability of pathogenicity of the p.Pro1776His variant is 0.00475, and classified the variant as likely neutral. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
Brotman Baty Institute, University of Washington	RCV001072702	SCV001238133	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro