ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.995G>A (p.Arg332Gln) (rs80357464)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000195399 SCV000077229 likely benign Hereditary breast and ovarian cancer syndrome 2020-12-02 criteria provided, single submitter clinical testing
Ambry Genetics RCV000129927 SCV000184745 likely benign Hereditary cancer-predisposing syndrome 2019-02-25 criteria provided, single submitter clinical testing in silico models in agreement (benign);Other strong data supporting benign classification
GeneDx RCV000049216 SCV000210096 uncertain significance not provided 2017-12-14 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.995G>A at the cDNA level, p.Arg332Gln (R332Q) at the protein level, and results in the change of an Arginine to a Glutamine (CGG>CAG). Using alternate nomenclature, this variant would be defined as BRCA1 1114G>A or 1227G>A. This variant was observed in at least one Portuguese breast and/or ovarian cancer family and in at least two Chinese breast cancer patients (Peixoto 2006, Peixoto 2014, Sun 2014). BRCA1 Arg332Gln was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Arginine and Glutamine differ in some properties, this is considered a semi-conservative amino acid substitution. BRCA1 Arg332Gln is located in a region known to interact with multiple other proteins (Paul 2014). In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure or function. Based on currently available information, it is unclear whether BRCA1 Arg332Gln is pathogenic or benign. We consider it to be a variant of uncertain significance.
Counsyl RCV000111525 SCV000488037 uncertain significance Breast-ovarian cancer, familial 1 2015-12-22 criteria provided, single submitter clinical testing
Mendelics RCV000195399 SCV000839292 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
Color Health, Inc RCV000129927 SCV000903088 likely benign Hereditary cancer-predisposing syndrome 2016-10-17 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000780998 SCV000918743 uncertain significance not specified 2020-10-12 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.995G>A (p.Arg332Gln) results in a conservative amino acid change in the encoded protein sequence. Four of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 251440 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.995G>A has been reported in the literature in individuals affected with Breast and/or Ovarian Cancer Syndrome (e.g. Judkins_2005, Peixoto_2006, Sun_2014, Shi_2017, Chan_2018). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign n=2, VUS n=5). Based on the evidence outlined above, the variant was classified as uncertain significance.
Mendelics RCV000111525 SCV001140614 uncertain significance Breast-ovarian cancer, familial 1 2019-05-28 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000111525 SCV000143976 uncertain significance Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing

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