ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.4599A>C (p.Lys1533Asn) (rs80358694)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000044452 SCV000072465 likely benign Hereditary breast and ovarian cancer syndrome 2020-12-04 criteria provided, single submitter clinical testing
Ambry Genetics RCV000129285 SCV000184046 likely benign Hereditary cancer-predisposing syndrome 2018-08-21 criteria provided, single submitter clinical testing Co-occurence with mutation in same gene (phase unknown);In silico models in agreement (benign)
GeneDx RCV000212237 SCV000210608 likely benign not specified 2018-02-08 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Counsyl RCV000077330 SCV000488129 uncertain significance Breast-ovarian cancer, familial 2 2016-01-06 criteria provided, single submitter clinical testing
A.C.Camargo Cancer Center / LGBM, A.C.Camargo Cancer Center RCV000413529 SCV000492494 uncertain significance Breast neoplasm criteria provided, single submitter research
Quest Diagnostics Nichols Institute San Juan Capistrano RCV001281727 SCV000600596 likely benign not provided 2020-01-08 criteria provided, single submitter clinical testing
Color Health, Inc RCV000129285 SCV000903090 benign Hereditary cancer-predisposing syndrome 2016-11-04 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001109714 SCV001267077 uncertain significance Fanconi anemia, complementation group D1 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Clinical Services Laboratory,Illumina RCV000077330 SCV001267078 uncertain significance Breast-ovarian cancer, familial 2 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Sharing Clinical Reports Project (SCRP) RCV000077330 SCV000109127 likely benign Breast-ovarian cancer, familial 2 2012-04-20 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000077330 SCV000146456 uncertain significance Breast-ovarian cancer, familial 2 2002-06-20 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353885 SCV000591913 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The BRCA2 p.Lys1533Asn variant was identified in 4 of 2316 proband chromosomes (frequency: 0.002) from individuals or families with breast cancer and was present in 1 of 638 control chromosomes (frequency: 0.02) from healthy individuals (Haffty 2009, Ho Choi 2004, Silva 2014, Suter 2004). The variant was also identified in dbSNP (ID: rs80358694) as “With other allele”, in ClinVar (classified as likely benign by Ambry Genetics, GeneDx, Invitae, COGR, SCRP; as uncertain significance by Counsyl, BIC and two clinical laboratories), Clinvitae, GeneInsight-COGR, Cosmic, and BIC Database (unknown clinical importance). The variant was not identified in LOVD 3.0, UMD-LSDB, ARUP Laboratories, or Zhejiang University database. The variant was identified in control databases in 24 of 276676 chromosomes at a frequency of 0.0001 (Genome Aggregation Database Feb 27, 2017). The variant was specifically observed in the East Asian population in 24 of 18864 chromosomes (freq: 0.001), while the variant was not observed in the African, Other, Latino, European, Ashkenazi Jewish, Finnish, and South Asian populations. The p.Lys1533 residue is not conserved in mammals 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. 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. This variant is classified as a variant of uncertain significance.

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