ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.10154G>A (p.Arg3385His) (rs80358398)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001086927 SCV000071735 likely benign Hereditary breast and ovarian cancer syndrome 2020-12-04 criteria provided, single submitter clinical testing
Ambry Genetics RCV000162743 SCV000213215 benign Hereditary cancer-predisposing syndrome 2015-06-23 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other data supporting benign classification
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000768613 SCV000324844 likely benign Breast and/or ovarian cancer 2015-09-11 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000725588 SCV000337948 uncertain significance not provided 2015-11-24 criteria provided, single submitter clinical testing
GeneDx RCV000725588 SCV000512405 likely benign not provided 2019-11-26 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 22752604, 20960228)
Color Health, Inc RCV000162743 SCV000910750 benign Hereditary cancer-predisposing syndrome 2016-04-21 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000374528 SCV000916866 likely benign not specified 2021-05-07 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.10154G>A (p.Arg3385His) 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 1.6e-05 in 251270 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.10154G>A has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome and other cancer phenotypes (examples- Kote-Jarai _2011, Laitman _2011, Juwle_2012, Lu_2015). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At least one co-occurrence with another pathogenic variant has been reported (BRCA2 c.7558C>T, p.Arg2520X; UMD database), providing supporting evidence for a benign role. A high-throughput study assessing sensitivity to four different poly (ADP-ribose) polymerase (PARP) inhibitors as an estimate of homology directed repair (HDR) functionality in-vitro indicated that cells with the p.Arg3385His variant had viability levels similar to wild-type, suggesting that HDR activity was retained,and providing evidence for a benign role for the variant (e.g. Ikegami_2020). Eight other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, citing the variant as benign/likely benign (n=6) and uncertain significance (n=2). We have tracked this variant for seven years at our laboratory (2014-2021) and no convincing evidence supporting a pathogenic outcome has emerged in this time frame. Based on the evidence outlined above, and in agreement with the majority consensus in the field, the variant was classified as Likely Benign.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000725588 SCV001470189 uncertain significance not provided 2019-11-07 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000031303 SCV000053908 benign Breast-ovarian cancer, familial 2 2012-03-29 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000031303 SCV000145761 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 RCV001353958 SCV000592314 likely benign Malignant tumor of breast no assertion criteria provided clinical testing The BRCA2 p.Arg3385His variant was identified in 2 of 2626 proband chromosomes (frequency: 0.0008) from individuals or families with breast and ovarian cancer (Laitman 2011, Cunningham 2014). The variant was also identified in ClinVar (as benign by Ambry Genetics and SCRP, as likely benign by CHEO and GeneDx, as uncertain significance by Emory Genetics, Invitae and BIC), Genesight-COGR (as likely benign by CHEO), LOVD 3.0 (1x, function effect unknown, and unclassified), UMD (1x as VUS), BIC (3x, classification pending) databases. The variant was not identified in Cosmic, MutDB, ARUP Laboratories and Zhejiang Colon Cancer Databases. The variant was identified in control databases in 4 of 245946 chromosomes at a frequency of 0.00002 increasing the likelihood that this may be a low frequency benign variant in certain populations of origin (Genome Aggregation Consortium Feb 27, 2017). The p.Arg3385 residue is not conserved in mammals and the variant amino acid histamine (His) is present in dog, increasing the likelihood that this variant does not have clinical significance. In addition 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 the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
True Health Diagnostics RCV000162743 SCV000787915 likely benign Hereditary cancer-predisposing syndrome 2017-09-29 no assertion criteria provided clinical testing

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