Submissions for variant NM_000059.4(BRCA2):c.8187G>T (p.Lys2729Asn)

gnomAD frequency: 0.00032  dbSNP: rs80359065

Total submissions: 25

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, susceptibility to, 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 ovarian cancer syndrome	2024-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000129090	SCV000183800	benign	Hereditary cancer-predisposing syndrome	2014-11-19	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Counsyl	RCV000113885	SCV000220904	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2014-11-21	criteria provided, single submitter	literature only
Michigan Medical Genetics Laboratories, University of Michigan	RCV000113885	SCV000267817	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2016-04-21	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000120363	SCV000301777	benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, 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 Laboratory Services, Illumina	RCV000113885	SCV000383782	likely benign	Breast-ovarian cancer, familial, susceptibility to, 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 Diagnostics, LLC DBA Color Health	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, susceptibility to, 2	2019-05-28	criteria provided, single submitter	clinical testing
Molecular Endocrinology Laboratory, Christian Medical College	RCV000113885	SCV002004016	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2		criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000735610	SCV002043533	likely benign	Breast and/or ovarian cancer	2021-06-02	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000129090	SCV002531921	benign	Hereditary cancer-predisposing syndrome	2020-06-10	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000120363	SCV002551801	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000113885	SCV004016887	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2023-07-07	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003476912	SCV004220592	benign	not provided	2022-11-22	criteria provided, single submitter	clinical testing
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, susceptibility to, 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, susceptibility to, 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
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000120363	SCV001953597	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000120363	SCV001968934	benign	not specified		no assertion criteria provided	clinical testing
Center for Precision Medicine, Meizhou People's Hospital	RCV002250493	SCV002520840	likely benign	Familial cancer of breast		no assertion criteria provided	literature only