Submissions for variant NM_007294.4(BRCA1):c.2351C>T (p.Ser784Leu)

gnomAD frequency: 0.00004  dbSNP: rs55914168

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031045	SCV001161494	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2019-06-18	reviewed by expert panel	curation	IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.000071
Invitae	RCV001082662	SCV000075822	likely benign	Hereditary breast ovarian cancer syndrome	2024-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000131345	SCV000186320	likely benign	Hereditary cancer-predisposing syndrome	2019-04-15	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.
GeneDx	RCV000587427	SCV000210129	likely benign	not provided	2020-05-18	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 16683254, 16267036, 16518693, 12531920, 15726418, 15001988, 25782689, 25652403, 25348012, 15385441)
Counsyl	RCV000031045	SCV000487970	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2015-12-18	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001255218	SCV000698944	benign	not specified	2020-08-25	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.2351C>T (p.Ser784Leu) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. These in silico predictions have not been verified with functional studies, with one study classifying the variant as benign, based on a homozygous occurrence in a patient derived LCL sample, and therefore using it as a control in the study (Loke_2015). The variant allele was found at a frequency of 0.00018 in 250640 control chromosomes, predominantly at a frequency of 0.0012 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 1.2 fold of the estimated maximal expected allele frequency for a pathogenic variant in BRCA1 causing Hereditary Breast and Ovarian Cancer Syndrome (HBOC) phenotype (0.001), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. The variant, c.2351C>T, has been reported in the literature in individuals affected with tumors that belong to the HBOC spectrum, but without strong evidence for causality (e.g. Judkins_2005, McKean-Cowdin_2005, van der Hout_2006, Li_2018, Shao_2019, Abe_2019), moreover, in some of these studies, it was also found in healthy controls (McKean-Cowdin_2005, Li_2018). Co-occurrences with other pathogenic variants have been reported (BRCA1 c.942_956delinsCTTACTTC (p.Arg1315fsX24) and RB1 c.1411C>T (p.Gln471X), in two internal LCA samples), providing supporting evidence for a benign role. In addition, a recent multifactorial likelihood analysis predicted this variant to be Benign (Parsons_2019). Eight other submitters, including an expert panel (ENIGMA), have provided clinical-significance assessments for this variant in ClinVar after 2014, and classified the variant as VUS (3x), likely benign (3x), or benign (2x; including the expert panel). Based on the evidence outlined above, the variant was classified as benign.
Color Diagnostics, LLC DBA Color Health	RCV000131345	SCV000902866	likely benign	Hereditary cancer-predisposing syndrome	2016-02-22	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000587427	SCV001133525	benign	not provided	2023-07-20	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000131345	SCV002538111	likely benign	Hereditary cancer-predisposing syndrome	2021-04-29	criteria provided, single submitter	curation
PreventionGenetics, part of Exact Sciences	RCV003415749	SCV004106584	uncertain significance	BRCA1-related condition	2023-06-22	criteria provided, single submitter	clinical testing	The BRCA1 c.2351C>T variant is predicted to result in the amino acid substitution p.Ser784Leu. This patient is heterozygous in the BRCA1 gene for a sequence variant defined as c.2351C>T, which is predicted to result in the amino acid substitution p.Ser784Leu. This variant has been reported in the Breast Cancer Information Core database (Szabo et al. 2000. PubMed ID: 10923033; Fleming et al. 2003. PubMed ID: 12531920). It has also been reported as a variant of uncertain significance in patients with hereditary breast, ovarian, colon, and/or prostate cancers (McKean-Cowdin et al. 2005. PubMed ID: 15726418; van der Hout et. al 2006. PubMed ID: 16683254; Judkins et al. 2005. PubMed ID: 16267036; Table A3, Abe et al. 2019. PubMed ID: 30883245; Table S2, Shao et al. 2019. PubMed ID: 31742824). Of note, this variant has also been reported in control populations (McKean-Cowdin et al. 2005. PubMed ID: 15726418) and is reported in 0.12% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-41245197-G-A) and is listed in ClinVar with conflicting interpretations of likely benign and uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/37464/). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV001255218	SCV004242834	benign	not specified	2024-02-06	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000031045	SCV000053639	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2009-08-28	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000031045	SCV000144388	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2002-05-29	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356396	SCV001551554	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA1 p.Ser784Leu variant was identified in 3 of 4154 proband chromosomes (frequency: 0.0007) from individuals or families with hereditary breast and ovarian cancer and was present in 18 of 11,404 control chromosomes (frequency: 0.001) from healthy individuals (McKean-Cowdin 2005,van der Hout 2006, Li 2018, Fernandez-Lopez 2019). The variant was identified in dbSNP (rs55914168) as “with likely pathogenic, other allele”, ClinVar (classified as likely benign by Ambry Genetics, Invitae, Color and 2 other submitters and uncertain significance by GeneDx, Counsyl and 3 other submitters), LOVD 3.0 (observed 15x), UMD-LSDB (observed 2x). The variant was identified in control databases in 45 of 282,304 chromosomes at a frequency of 0.0002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Latino in 43 of 33,396 chromosomes (freq: 0.001, increasing the likelihood this could be a low frequency benign variant), African in 1 of 24,966 chromosomes (freq: 0.00004), European in 1 of 128,600 chromosomes (freq: 0.000008); it was not observed in the Other, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.Ser784 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, 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 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. 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.