ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.8187G>T (p.Lys2729Asn) (rs80359065)

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Total submissions: 18
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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) RCV000113885 SCV000244483 benign Breast-ovarian cancer, familial 2 2015-08-10 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 = 0.0000165. Also class 1 based on frequency >1% in an outbred sampleset. Frequency 0.01224 (Asian), derived from 1000 genomes (2012-04-30).
Invitae RCV000045445 SCV000073458 benign Hereditary breast and ovarian cancer syndrome 2020-12-06 criteria provided, single submitter clinical testing
Ambry Genetics RCV000129090 SCV000183800 benign Hereditary cancer-predisposing syndrome 2014-11-19 criteria provided, single submitter clinical testing General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance
Counsyl RCV000113885 SCV000220904 benign Breast-ovarian cancer, familial 2 2014-11-21 criteria provided, single submitter literature only
Michigan Medical Genetics Laboratories,University of Michigan RCV000113885 SCV000267817 benign Breast-ovarian cancer, familial 2 2016-04-21 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000120363 SCV000301777 benign not specified criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000009925 SCV000383781 likely benign Fanconi anemia, complementation group D1 2019-01-10 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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Clinical Services Laboratory,Illumina RCV000113885 SCV000383782 likely benign Breast-ovarian cancer, familial 2 2019-01-10 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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Color Health, Inc RCV000129090 SCV000683950 benign Hereditary cancer-predisposing syndrome 2015-04-13 criteria provided, single submitter clinical testing
Mendelics RCV000113885 SCV001139209 likely benign Breast-ovarian cancer, familial 2 2019-05-28 criteria provided, single submitter clinical testing
Research and Development, ARUP Laboratories RCV001642472 SCV001852783 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
OMIM RCV000009925 SCV000030146 pathogenic Fanconi anemia, complementation group D1 2002-07-26 no assertion criteria provided literature only
Sharing Clinical Reports Project (SCRP) RCV000113885 SCV000054332 benign Breast-ovarian cancer, familial 2 2011-03-14 no assertion criteria provided clinical testing
ITMI RCV000120363 SCV000084515 not provided not specified 2013-09-19 no assertion provided reference population
Breast Cancer Information Core (BIC) (BRCA2) RCV000113885 SCV000147296 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 RCV001353739 SCV000592178 benign Malignant tumor of breast no assertion criteria provided clinical testing The p.Lys2729Asn variant is identified in the literature in at least 13 of 5204 proband chromosomes (frequency 0.002) in individuals with breast, ovarian, esophageal and hepatocelllar carcinoma, and in 7 of 1546 healthy control chromosomes (frequency 0.005); the elevated frequency in controls increases the likelihood that this variant is benign (Katagiri 1996, Zhi 2002, Hu 2004, Kawahara 2004, Ang 2007, Syamala 2007, Thirthagiri 2008, Lim 2009, Kaushal 2010, Akbari 2011). It is listed in the dbSNP database (ID# rs80359065) with a minor allele frequency of 0.003 (1000 genomes), also increasing the likelihood that this is a low frequency benign variant. Another variant at the same position, c.8187G>C, results in the same amino acid change and was reported in the UMD database in the presence of a second "pathogenic" variant, suggesting this variant may not have clinical significance. There was conflicting evidence in the literature as to the clinical significance of this variant. The p.Lys2729Asn variant was identified as co-occuring with a deleterious mutation, p.S2835X, in the BRCA2 gene in an acute myelogenous leukemia cell line from a Fanconi anemia patient (Howlett 2002, Ikeda 2003, Alter 2007). This suggests that the p.Lys2729Asn variant may play a role in this disorder whereby two BRCA2 mutations are required for disease progression, consistent with autosomal recessive inheritance. However, the p.Lys2729 residue is not highly conserved in mammals and computational analyses (PolyPhen2, SIFT, AlignGVGD, BLOSUM) provide inconsistent predictions regarding the impact to the protein, leaning more towards pathognic, but this information is not predictive enough to assume pathogenicity. This variant has been reported to have 614:1 odds in favour of neutrality (Easton 2007) and a recent functional study suggests that it is a neutral variant (Farrugia 2008). In addition, Biswas et al. (2011) recently carried out functional studies to show it is neutral variant. Furthermore, Myriad genetics classifies this variant as a polymorphism (personal communication). In summary, based on the above information this variant is classified as Benign.
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research RCV000735610 SCV000863748 benign Breast and/or ovarian cancer 2013-02-14 no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000120363 SCV001953597 benign not specified no assertion criteria provided clinical testing

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