ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.4670C>G (p.Thr1557Ser) (rs80358698)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001084564 SCV000072480 benign Hereditary breast and ovarian cancer syndrome 2020-12-06 criteria provided, single submitter clinical testing
Ambry Genetics RCV000132179 SCV000187258 benign Hereditary cancer-predisposing syndrome 2015-05-14 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 RCV000588262 SCV000512361 likely benign not provided 2020-09-17 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 16826315, 24607278, 14684619, 15937982, 27157322, 22476429, 31131967, 31825140)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000588262 SCV000694794 benign not provided 2016-03-31 criteria provided, single submitter clinical testing Variant Summary: The c.4670C>G variant in BRCA2 gene is a missense change that alters a non-conserved and 4/5 in silico tools predict benign outcome. The variant is found in the large control population dataset of ExAC at a frequency of 0.003%. This frequency does not exceed the maximal expected frequency of a pathogenic allele (0.075%), however the variant may be a rare functional polymorphism. The variant has been reported in several affected individuals without strong evidence for causality. The fact that c.4670C>G has been reported to co-occur with a different deleterious mutation in BRCA1 and BRCA2 genes including presence of another deleterious variant in trans and failed to segregate with the disease in at least one HBOC family suggests a non-disease causing nature of this variant. In addition, reputable databases/diagnostic centers listed the variant of interest with a classification of Benign/Likely Benign. Considering all evidence, the variant was classified as Benign.
Counsyl RCV000031498 SCV000785726 likely benign Breast-ovarian cancer, familial 2 2017-11-08 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000588262 SCV000889059 likely benign not provided 2018-03-28 criteria provided, single submitter clinical testing
Color Health, Inc RCV000132179 SCV000911090 benign Hereditary cancer-predisposing syndrome 2016-02-17 criteria provided, single submitter clinical testing
Mendelics RCV000031498 SCV001139095 likely benign Breast-ovarian cancer, familial 2 2019-05-28 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000031498 SCV000054103 benign Breast-ovarian cancer, familial 2 2012-05-01 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000031498 SCV000146466 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 RCV001353754 SCV000591918 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The BRCA2 p.Thr1557Ser variant was identified in 3 of 1662 proband chromosomes (frequency 0.002) from individuals or families with breast cancer; it was not identified in any of the 288 control chromosomes evaluated (Esteban-Cardenosa 2004, Peixoto 2006, Velasco 2005). This variant was also previously identified by our lab in an individual with breast cancer. It is listed in dbSNP database as coming from a "clinical source" (ID#: rs80358698) with a global minor allele frequency (MAF) of 0.001 (1000 Genomes); however, there was only one observation and it was not validated. It has also been reported in the UMD (7X as an unclassified variant), and in the BIC database (5X with unknown clinical importance). This residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM) do not suggest a high likelihood of impact to the protein. However, this information is not predictive enough to rule out 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 unknown significance.
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research RCV000735553 SCV000863691 uncertain significance Breast and/or ovarian cancer 2012-10-01 no assertion criteria provided clinical testing

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