ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.2320A>G (p.Thr774Ala) (rs55968715)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000225743 SCV000071987 benign Hereditary breast and ovarian cancer syndrome 2020-12-03 criteria provided, single submitter clinical testing
Ambry Genetics RCV000131357 SCV000186333 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.
GeneDx RCV000120313 SCV000210576 likely benign not specified 2017-05-17 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Michigan Medical Genetics Laboratories,University of Michigan RCV000031362 SCV000267752 likely benign Breast-ovarian cancer, familial 2 2016-04-21 criteria provided, single submitter clinical testing
Counsyl RCV000031362 SCV000488277 uncertain significance Breast-ovarian cancer, familial 2 2016-02-12 criteria provided, single submitter clinical testing
Color Health, Inc RCV000131357 SCV000902773 benign Hereditary cancer-predisposing syndrome 2016-08-01 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000120313 SCV000919040 benign not specified 2021-02-07 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.2320A>G (p.Thr774Ala) 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. The variant allele was found at a frequency of 4e-05 in 250976 control chromosomes, predominantly at a frequency of 7.1e-05 within the Non-Finnish European subpopulation in the gnomAD database. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2320A>G has been reported in the literature in individuals affected with Breast or Prostate cancer and Ovarian Cancer as well as in a patient with macrocytic thrombocytopenia (example, Haiman_2013, Cunningham_2014, Kager_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Multiple co-occurrences with other pathogenic variant(s) have been reported in public databases such as UMD and BIC as well as our laboratory (UMD-BRCA2 c.5576_5579delTTAA, p.Ile1859fsX3; BRCA1 c.3700_3704delGTAAA, p.Val1234GlnfsX8; BRCA1 c.4065_4068delTCAA, p.Asn1355LysfsX10; BIC-BRCA1 c.3255_3256insGA, p.Arg1085_Leu1086?fs; Our laboratory-BRCA1 c.2722G>T, p.Glu908X), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely benign/benign, n=6; VUS, n=1). Based on the evidence outlined above, the variant was classified as benign.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000120313 SCV001159027 likely benign not specified 2018-07-02 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000031362 SCV000053967 benign Breast-ovarian cancer, familial 2 2009-11-19 no assertion criteria provided clinical testing
ITMI RCV000120313 SCV000084465 not provided not specified 2013-09-19 no assertion provided reference population
Breast Cancer Information Core (BIC) (BRCA2) RCV000031362 SCV000146027 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 RCV000120313 SCV000591799 benign not specified no assertion criteria provided clinical testing The BRCA2 p.Thr774Ala variant was not identified in the literature. The variant was identified in dbSNP (ID: rs55968715), the ClinVar database (classified as a benign variant by Ambry Genetics and by the Sharing Clinical Reports Project (derived from Myriad reports)), the BIC database (6X with unknown clinical importance), and UMD (3X as an unclassified variant). In UMD the variant was identified in one sample with a co-occurring pathogenic BRCA2 variant (c.5576_5579delTTAA (p.Ile1859LysfsX3)) and in another sample with a co-occurring pathogenic BRCA1 variant (c.4065_4068delTCAA (p.Asn1355LysfsX10), increasing the likelihood that the p.Thr774Ala variant does not have clinical significance. The variant was identified by the Exome Variant Server project in 1 of 8600 European American alleles (frequency: 0.0001), 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 p.Thr774 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. In addition, 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. However, this information is not predictive enough to rule out pathogenicity. In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign.
True Health Diagnostics RCV000131357 SCV000787923 likely benign Hereditary cancer-predisposing syndrome 2017-07-12 no assertion criteria provided clinical testing

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