ClinVar Miner

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

gnomAD frequency: 0.00004  dbSNP: rs80358803
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Total submissions: 17
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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, susceptibility to, 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
Labcorp Genetics (formerly Invitae), Labcorp RCV001081769 SCV000072756 benign Hereditary breast ovarian cancer syndrome 2024-01-26 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: 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.
Counsyl RCV000077359 SCV000220254 likely benign Breast-ovarian cancer, familial, susceptibility to, 2 2014-04-17 criteria provided, single submitter literature only
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 likely benign not provided 2023-08-23 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000168582 SCV000694899 likely benign not specified 2022-02-12 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. This frequency is not significantly higher than expected for a pathogenic variant in BRCA2 causing Hereditary Breast And Ovarian Cancer Syndrome (4.4e-05 vs 0.00075), allowing no conclusion about variant significance. c.5752C>T has been reported in the literature with varying classifications ranging from VUS/neutral/likely benign/benign among individuals with breast/prostate/ovarian cancer (example, Kote-Jarai_2011, Lu_2015, Ernst_2018, Lebo_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. 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). At-least one co-occurrence with another pathogenic variant has been observed at our laboratory (BRCA2 c.5946delT, p.Ser1982fsX22), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Multiple clinical diagnostic laboratories and en expert panel (ENIGMA) have submitted conflicting clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS, n=2; benign/likely benign, n=6 to include the expert panel). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely benign.
Color Diagnostics, LLC DBA Color Health RCV000163008 SCV000910732 benign Hereditary cancer-predisposing syndrome 2015-12-08 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Mass General Brigham 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 Laboratory Services, Illumina RCV000077359 SCV001267162 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 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 Laboratory Services, 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.
Sema4, Sema4 RCV000163008 SCV002536172 likely benign Hereditary cancer-predisposing syndrome 2021-01-07 criteria provided, single submitter curation
Sharing Clinical Reports Project (SCRP) RCV000077359 SCV000109156 likely benign Breast-ovarian cancer, familial, susceptibility to, 2 2011-02-24 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000077359 SCV000146689 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 2 2002-05-29 no assertion criteria provided clinical testing
PreventionGenetics, part of Exact Sciences RCV004528246 SCV000301766 likely benign BRCA2-related disorder 2024-01-30 no assertion criteria provided clinical testing This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
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.

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