Submissions for variant NM_000059.4(BRCA2):c.352C>T (p.Arg118Cys)

gnomAD frequency: 0.00004  dbSNP: rs375125172

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129600	SCV000184384	likely benign	Hereditary cancer-predisposing syndrome	2018-11-08	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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.
GeneDx	RCV000590557	SCV000210234	uncertain significance	not provided	2023-05-16	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast cancer, some of whom had additional variants that may explain their phenotype (Zhong et al., 2016; Andrikopoulou et al., 2022; Zografos et al., 2022); Published functional studies demonstrate aberrant splicing in a minority of transcripts (Fraile-Bethencourt et al., 2019); Also known as 580C>T; This variant is associated with the following publications: (PMID: 27257965, 31131967, 30702160, 25846551, 11948123, 35127508, 36011273, 30287823, 33471991, 34313030, 31825140, 30883759)
Invitae	RCV000168454	SCV000219151	likely benign	Hereditary breast ovarian cancer syndrome	2024-01-10	criteria provided, single submitter	clinical testing
Laboratory of Molecular Diagnosis of Cancer, West China Hospital, Sichuan University	RCV000240706	SCV000265924	uncertain significance	Breast neoplasm	2015-11-01	criteria provided, single submitter	research
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000160016	SCV000602799	uncertain significance	not specified	2018-09-11	criteria provided, single submitter	clinical testing	The BRCA2 c.352C>T; p.Arg118Cys variant (rs375125172), is reported in the literature in at least one individual affected with breast cancer (Zhong 2016). This variant is reported with conflicting classifications in ClinVar (Variation ID: 91803), and is found in the African population with an overall allele frequency of 0.03% (4/15,298 alleles) in the Genome Aggregation Database. The arginine at codon 118 is weakly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Due to limited information, the clinical significance of the p.Arg118Cys variant is uncertain at this time. References: Zhong X et al. Prevalence and Prognostic Role of BRCA1/2 Variants in Unselected Chinese Breast Cancer Patients. PLoS One. 2016 Jun 3;11(6):e0156789.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000160016	SCV000694701	uncertain significance	not specified	2023-03-21	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.352C>T (p.Arg118Cys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. 4/4 computational tools via ALAMUT predict no significant impact on normal splicing although a disruption of an ESE splice site is predicted. In a minigene assay system, this variant was reported to produce 74% of the canonical transcript and low levels of delta 4, delta 4,5 and delta 4,5,6 transcripts (Fraile-Bethencourt_2019). However, the in-vivo impact of these findings have yet to be corroborated by functional studies. The variant allele was found at a frequency of 4e-05 in 251000 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in BRCA2 causing Hereditary Breast and Ovarian Cancer (4e-05 vs 0.00075), allowing no conclusion about variant significance. c.352C>T has been reported in the literature in individuals affected with Breast Cancer without strong evidence for causality (Zhang_2016, Bhaskaran_2019). Co-occurrences with other pathogenic variant(s) have been reported (BRCA1 c. 3700_3704del, p. Val1234Glnfs*8; Zografos_2022), providing supporting evidence for a benign role. These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (3 likely benign, 7 VUS) . Based on the evidence outlined above, the variant was classified as uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000129600	SCV000911378	likely benign	Hereditary cancer-predisposing syndrome	2015-12-08	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000590557	SCV001133762	uncertain significance	not provided	2023-05-14	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.00025 (4/16246 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with breast cancer (PMID: 27257965 (2016), 30702160 (2019), 36011273 (2022)) and unaffected individuals (PMID: 30287823 (2018), 33471991 (2021)). This variant was found to impact splicing in one study (PMID: 30883759 (2019)) but published functional studies describing its effect on protein function have not been found. 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 deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Division of Medical Genetics, University of Washington	RCV000077711	SCV001434309	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2020-01-22	criteria provided, single submitter	clinical testing	This variant has been reported in the literature in individuals with breast cancer (Zhong 2016, Bhaskaran 2019). This variant has an overall allele frequency of 0.00003 in the Broad Institute gnomAD Browser (https://gnomad.broadinstitute.org/). In silico analyses indicate that this variant does not alter protein structure/function. Thus, it is unknown at this time whether this variant increases cancer risk. BP4
Genetic Services Laboratory, University of Chicago	RCV000160016	SCV002067793	uncertain significance	not specified	2020-02-13	criteria provided, single submitter	clinical testing	DNA sequence analysis of the BRCA2 gene demonstrated a sequence change, c.352C>T, in exon 4 that results in an amino acid change, p.Arg118Cys. This sequence change has been previously described in a patient with breast cancer but no additional information was provided (PMID: 27257965). This sequence change has been described in the gnomAD database with a low population frequency of 0.025% in the African subpopulation (dbSNP rs375125172). The p.Arg118Cys change affects a poorly conserved amino acid residue located in a domain of the BRCA2 protein that is known to be functional. The p.Arg118Cys substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Arg118Cys change remains unknown at this time.
Sema4, Sema4	RCV000129600	SCV002533806	uncertain significance	Hereditary cancer-predisposing syndrome	2021-08-03	criteria provided, single submitter	curation
Baylor Genetics	RCV003474666	SCV004211791	uncertain significance	Familial cancer of breast	2023-10-30	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000077711	SCV000109514	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2006-12-06	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000590557	SCV001552321	uncertain significance	not provided		no assertion criteria provided	clinical testing	The BRCA2 p.Arg118Cys variant was not identified in the literature nor was it identified in the following databases: GeneInsight-COGR, MutDB, BIC, ARUP Laboratories, or Zhejiang Colon Cancer Database. The variant was identified in dbSNP (ID: rs375125172) as With Uncertain significance allele, ClinVar (classified as likely benign by Ambry Genetics; classified as uncertain significance by GeneDx, Invitae, SCRP), Cosmic (classified as Neutral (score 0.00)), LOVD 3.0, and UMD-LSDB (4X classified as unclassified variant). The variant was identified in control databases in 9 of 245844 chromosomes at a frequency of 0.000037 (Genome Aggregation Consortium Feb 27, 2017). The p.Arg118 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. The variant is located with the Breast cancer type 2 susceptibility protein functional domain, the clinical significance of which is uncertain. 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.