ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.4816A>G (p.Lys1606Glu) (rs80356943)

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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000031193 SCV001161595 benign Breast-ovarian cancer, familial 1 2019-06-18 reviewed by expert panel curation IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.000266
Invitae RCV000048668 SCV000076681 benign Hereditary breast and ovarian cancer syndrome 2020-12-02 criteria provided, single submitter clinical testing
Ambry Genetics RCV000130005 SCV000184830 uncertain significance Hereditary cancer-predisposing syndrome 2019-05-04 criteria provided, single submitter clinical testing The p.K1606E variant (also known as c.4816A>G), located in coding exon 14 of the BRCA1 gene, results from an A to G substitution at nucleotide position 4816. The lysine at codon 1606 is replaced by glutamic acid, an amino acid with similar properties. This variant was described in a patient with breast cancer before age 30 years, who had no family history of breast or ovarian cancer (FitzGerald MG et al. N. Engl. J. Med. 1996; 334:143-9). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000436368 SCV000219251 uncertain significance not specified 2017-07-28 criteria provided, single submitter clinical testing
GeneDx RCV001281714 SCV000512312 likely benign not provided 2020-10-20 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 30765603, 32546644, 28781887, 16267036, 8531968, 15004537, 16905680, 31131967)
Quest Diagnostics Nichols Institute San Juan Capistrano RCV001281714 SCV000605892 uncertain significance not provided 2019-09-01 criteria provided, single submitter clinical testing
Counsyl RCV000031193 SCV000785870 uncertain significance Breast-ovarian cancer, familial 1 2017-12-20 criteria provided, single submitter clinical testing
Color Health, Inc RCV000130005 SCV000903167 likely benign Hereditary cancer-predisposing syndrome 2017-03-22 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000436368 SCV000918792 likely benign not specified 2018-11-01 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.4816A>G (p.Lys1606Glu) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 246164 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4816A>G has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Fitzgerald_1996, Judkins_2005, Simard_2007). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Two independent publications spanning a decade report experimental evidence evaluating an impact on protein function, both of which demonstrate no functional impact of this variant on measures of yeast small colony phenotype assay (Coyne 2004) and a transcriptional activation assay coupled to a Bayesian hierarchical model that estimated the likelihood of pathogenicity (Woods, 2016). Six 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 (4 VUS, 2 likely benign/benign). Taken together, the emerging functional evidence surrounding this variant published in reputed recently published journals and recent classifications in data sharing databases (ClinVar) support the move towards a benign impact for this variant. However, additional evidence supporting presence in unaffected controls (due to its rarity), lack of co-seggregation with disease, and co-occurrences with other pathological variants in BRCA1 is awaited. Based on the evidence outlined above, the variant was classified as likely benign.
Mendelics RCV000031193 SCV001140508 benign Breast-ovarian cancer, familial 1 2019-05-28 criteria provided, single submitter clinical testing
Research and Development, ARUP Laboratories RCV001659864 SCV001878389 benign Breast-ovarian cancer, familial 2; Breast-ovarian cancer, familial 1; Hereditary breast and ovarian cancer syndrome 2020-01-20 criteria provided, single submitter curation
Sharing Clinical Reports Project (SCRP) RCV000031193 SCV000053793 likely benign Breast-ovarian cancer, familial 1 2012-05-01 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000031193 SCV000145189 uncertain significance Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000031193 SCV000591540 uncertain significance Breast-ovarian cancer, familial 1 no assertion criteria provided clinical testing The BRCA1 p.Lys1606Glu variant was identified in at least 9 of 111320 proband chromosomes from individuals with breast cancer or who were referred for BRCA1 screening (Fitzgerald 1996, Judkins 2005); however, control chromosomes were not evaluated in these studies, thus the prevalence of this variant in the general population could not be determined. This variant was previously identified by our lab in an individual with breast cancer, and was also identified in dbSNP (ID: rs80356943) “With untested allele”, HGMD, UMD (1X as an unknown variant), and the BIC database (8X with unknown clinical importance). This residue is not conserved in mammals or lower organisms and 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. 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 RCV000735492 SCV000863630 uncertain significance Breast and/or ovarian cancer no assertion criteria provided clinical testing

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