Submissions for variant NM_000059.4(BRCA2):c.5752C>T (p.His1918Tyr) (rs80358803)

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000077359	SCV000244460	benign	Breast-ovarian cancer, familial 2	2015-08-10	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 = 0.00000575
Invitae	RCV001081769	SCV000072756	benign	Hereditary breast and ovarian cancer syndrome	2020-12-03	criteria provided, single submitter	clinical testing
GeneDx	RCV000044743	SCV000210619	likely benign	not provided	2019-04-16	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016).; This variant is associated with the following publications: (PMID: 23704879, 24323938, 17924331, 21990134, 28866612)
Ambry Genetics	RCV000163008	SCV000213496	benign	Hereditary cancer-predisposing syndrome	2014-11-19	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
Counsyl	RCV000077359	SCV000220254	likely benign	Breast-ovarian cancer, familial 2	2014-04-17	criteria provided, single submitter	literature only
PreventionGenetics,PreventionGenetics	RCV000168582	SCV000301766	likely benign	not specified		criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000168582	SCV000593719	likely benign	not specified	2016-04-20	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000044743	SCV000600662	benign	not provided	2018-09-04	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000168582	SCV000694899	likely benign	not specified	2019-04-19	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.5752C>T (p.His1918Tyr) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.4e-05 in 251154 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in BRCA2 causing Hereditary Breast and Ovarian Cancer (4.4e-05 vs 0.00075), allowing no conclusion about variant significance. c.5752C>T has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer and also, prostate cancer (Ernst_2018, Lu_2015, Kote-Jarai_2011). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. A co-occurrence with a pathogenic variant has been reported (LabCorp; BRCA2 c.5946delT, p.Ser1982fsX22), providing supporting evidence for a benign role. In addition, studies utilizing multifactorial likelihood models to assess the clinical significance of BRCA2 variants predict this variant to be neutral/not pathogenic (Lindor_2012, Easton_2007). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six submitters including one expert panel have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and all have classified the variant as benign (n=2)/likely benign (n=4). Based on the evidence outlined above, the variant was classified as likely benign until additional clinical and functional data become available.
Color Health, Inc	RCV000163008	SCV000910732	benign	Hereditary cancer-predisposing syndrome	2015-12-08	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine	RCV000168582	SCV000966583	uncertain significance	not specified	2018-05-15	criteria provided, single submitter	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
Illumina Clinical Services Laboratory,Illumina	RCV000077359	SCV001267162	uncertain significance	Breast-ovarian cancer, familial 2	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Clinical Services Laboratory,Illumina	RCV001110578	SCV001268030	uncertain significance	Fanconi anemia, complementation group D1	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Research and Development, ARUP Laboratories	RCV001646432	SCV001854855	benign	Breast-ovarian cancer, familial 2; Breast-ovarian cancer, familial 1; Hereditary breast and ovarian cancer syndrome	2020-01-20	criteria provided, single submitter	curation
Sharing Clinical Reports Project (SCRP)	RCV000077359	SCV000109156	likely benign	Breast-ovarian cancer, familial 2	2011-02-24	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000077359	SCV000146689	uncertain significance	Breast-ovarian cancer, familial 2	2002-05-29	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System	RCV000168582	SCV000591998	benign	not specified		no assertion criteria provided	clinical testing	The BRCA2 p.His1918Tyr variant was identified dbSNP (ID: rs80358803) “With likely benign allele”, Clinvitae database (as “likely benign”), LOVD (as “predicted neutral”), ARUP Laboratories BRCA Mutations Database (as “not pathogenic”), the ClinVar database (classified as a benign variant reviewed by an expert panel), GeneInsight COGR database (classified 2X as “likely benign” 1X as “benign” and 1X “unclassified” ), the BIC database (9X with unknown clinical importance), and UMD (1X as an unknown variant). The variant was also identified by the Exome Aggregation Consortium (ExAC) database in 5 of 66606 (European (Non-Finnish)) alleles (frequency: 7.51X10-05), although this low number of observations and low frequency is not substantive enough to determine the prevalence of the variant in the general population and its relationship to disease.The variant was also identified by our laboratory in 1 individual with breast cancer. The variant was found in the literature, classified by several functional and in silico studies as benign (Easton 2007, Lindor 2012, Guidugli 2014).The p.His1918 residue is not conserved in mammals and 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. In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign.