Submissions for variant NM_007294.4(BRCA1):c.332A>C (p.Glu111Ala)

dbSNP: rs80357312

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000486172	SCV000573289	uncertain significance	not provided	2021-03-10	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 451A>C; Observed in individuals referred for hereditary breast and ovarian cancer testing (Pedersen 2018); This variant is associated with the following publications: (PMID: 23704879, 31131967, 29168416)
Ambry Genetics	RCV001020000	SCV001181422	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-18	criteria provided, single submitter	clinical testing	The p.E111A variant (also known as c.332A>C), located in coding exon 5 of the BRCA1 gene, results from an A to C substitution at nucleotide position 332. The glutamic acid at codon 111 is replaced by alanine, an amino acid with dissimilar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV001020000	SCV001345473	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-10	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with alanine at codon 111 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). To our knowledge, functional studies have not been reported for this variant. This variant has been detected in a breast cancer case-control meta-analysis in 0/60466 cases and 1/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_006581). A multifactorial analysis has reported likelihood ratios for pathogenicity based on co-occurrence with a pathogenic covariant and family history of 1.0331 and 0.6418, respectively. 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001315292	SCV001505861	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-11-10	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 111 of the BRCA1 protein (p.Glu111Ala). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with personal or family history of breast cancer (PMID: 36881271). ClinVar contains an entry for this variant (Variation ID: 54844). 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.
Mendelics	RCV002247442	SCV002517961	uncertain significance	not specified	2022-05-04	criteria provided, single submitter	clinical testing
Human Genetics Bochum, Ruhr University Bochum	RCV002463633	SCV002758578	uncertain significance	Endometrial carcinoma	2022-08-15	criteria provided, single submitter	clinical testing	ACMG criteria used to clasify this variant: PM5, PM2, BS3
All of Us Research Program, National Institutes of Health	RCV000112332	SCV004823673	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2023-05-04	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with alanine at codon 111 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). To our knowledge, functional studies have not been reported for this variant. This variant has been detected in a breast cancer case-control meta-analysis in 0/60466 cases and 1/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_006581). A multifactorial analysis has reported likelihood ratios for pathogenicity based on co-occurrence with a pathogenic covariant and family history of 1.0331 and 0.6418, respectively. 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.
Myriad Genetics, Inc.	RCV000112332	SCV004931004	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2024-03-11	criteria provided, single submitter	clinical testing	This variant is considered benign. This variant been observed in trans with a known pathogenic variant in one or more individuals. Compound heterozygosity for pathogenic variants in this gene is generally assumed to result in embryonic lethality. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
Breast Cancer Information Core (BIC) (BRCA1)	RCV000112332	SCV000145084	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2004-02-20	no assertion criteria provided	clinical testing
MVZ Praenatalmedizin und Genetik Nuernberg	RCV000112332	SCV000777894	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2018-05-01	no assertion criteria provided	clinical testing	This rare variant (gnomAD) was found in different databases with uncertain significance. In silico analyses show contradictory results. Therefore we rate this variant as Variant of unknown significance (VUS). Interestingly we found this variant in a patient who harbored also a pathogenic BRCA1-variant (BRCA1-Deletion of exon 1-6 heterozygous) in trans. Therefore the missense variant c.332A>C was found to be hemizygous and disagrees with a pathogenic effect.