ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.6803G>A (p.Arg2268Lys) (rs80358906)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001086840 SCV000073068 benign Hereditary breast and ovarian cancer syndrome 2020-12-04 criteria provided, single submitter clinical testing
Ambry Genetics RCV000131556 SCV000186558 benign Hereditary cancer-predisposing syndrome 2016-08-22 criteria provided, single submitter clinical testing Seen in trans with a mutation or in homozygous state in individual without severe disease for that gene
Michigan Medical Genetics Laboratories,University of Michigan RCV000077385 SCV000195999 uncertain significance Breast-ovarian cancer, familial 2 2014-11-03 criteria provided, single submitter clinical testing
GeneDx RCV000587611 SCV000210636 likely benign not provided 2021-06-11 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 23292937, 22682623, 22034289, 23555315, 31131967)
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000587611 SCV000225158 uncertain significance not provided 2015-03-12 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000587611 SCV000600719 likely benign not provided 2020-07-17 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000045055 SCV000694997 likely benign not specified 2021-06-10 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.6803G>A (p.Arg2268Lys) results in a conservative amino acid change located in the outside of any known functional domain or repeat of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 250550 control chromosomes, predominantly at a frequency of 0.00051 within the African or African-American subpopulation in the gnomAD database. The variant has also been observed in a database of unaffected cancer free individuals of African American ancestry at age greater than 70 (FLOSSIES database). c.6803G>A has been reported in the literature in sequencing studies of individuals affected with Breast and/or Ovarian Cancers (e.g. Dutil_2012, Fackenthal_2012, Haiman_2013, Balmaa_2016). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Co-occurrences with other pathogenic variants have been reported ( BRCA1 c.815_824dupAGCCATGTGG , p.Thr276fsX14) (BIC database), including one publication that reported a co-occurrence with an unspecified deleterious mutation (Dutil_2012) providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=1), likely benign (n=4) and benign (n=2). Based on the evidence outlined above, the variant was classified as likely benign.
Color Health, Inc RCV000131556 SCV000902982 likely benign Hereditary cancer-predisposing syndrome 2016-04-28 criteria provided, single submitter clinical testing
Mendelics RCV000077385 SCV001139157 likely benign Breast-ovarian cancer, familial 2 2019-05-28 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000077385 SCV000109182 benign Breast-ovarian cancer, familial 2 2010-12-28 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000077385 SCV000146938 uncertain significance Breast-ovarian cancer, familial 2 2004-02-20 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353618 SCV000592075 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The p.Arg2268Lys variant has been previously identified in 1 out of 802 proband chromosomes (frequency 0.001) of individuals with unselected breast cancers, but was not studied in control populations (Fackenthal 2012). It is listed in dbSNP database as coming from a "clinical source" (ID#: rs80358906) with an average heterozygosity of 0.002+/-0.028, increasing the likelihood this variant is benign. However, this variant is also listed in the BIC database three times with unknown clinical importance. The p.Ala2268 residue is conserved in mammals, however in silico computational analyses (SIFT and AignGVGD) do not suggest a high likelihood of impact to the protein. In summary, 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 a variant of unknown significance.

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