Submissions for variant NM_000059.4(BRCA2):c.964A>C (p.Lys322Gln) (rs11571640)

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000045881	SCV000073894	benign	Hereditary breast and ovarian cancer syndrome	2020-12-06	criteria provided, single submitter	clinical testing
GeneDx	RCV000034472	SCV000108650	likely benign	not provided	2020-02-21	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 8840963, 25802882, 20104584, 23729402, 24884479, 26332594, 22703879, 21520273, 19016756, 21218378, 15168169, 27600092, 22771033, 28111427, 26692440, 29770616, 30415210, 29802286, 31131967)
Ambry Genetics	RCV000131239	SCV000186196	benign	Hereditary cancer-predisposing syndrome	2015-03-01	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	RCV000031841	SCV000220806	likely benign	Breast-ovarian cancer, familial 2	2014-10-16	criteria provided, single submitter	literature only
Soonchunhyang University Bucheon Hospital,Soonchunhyang University Medical Center	RCV000031841	SCV000267232	uncertain significance	Breast-ovarian cancer, familial 2	2016-03-18	criteria provided, single submitter	reference population
A.C.Camargo Cancer Center / LGBM, A.C.Camargo Cancer Center	RCV000414578	SCV000492490	uncertain significance	Breast neoplasm		criteria provided, single submitter	research
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine	RCV000074565	SCV000538478	likely benign	not specified	2016-10-27	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant has been reported in 11 patients with breast cancer (7 of whom were Asian), 1 patient with hepatocellular carcinoma, and 1 patient with no history of cancer. It is present in ExAC with a Max MAF of 0.35%. At this frequency a pathogenic role is unlikely. It is classified as LB/B by 5 submitters in ClinVar with 1 star (Invitae, GeneDx, Ambry, Counsyl, SCRP) and as VUS by BIC and Biesecker lab.
Color Health, Inc	RCV000131239	SCV000684083	likely benign	Hereditary cancer-predisposing syndrome	2016-11-03	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000034472	SCV000695260	likely benign	not provided	2017-02-09	criteria provided, single submitter	clinical testing	Variant summary: The BRCA2 c.964A>C (p.Lys322Gln) variant involves the alteration of a conserved nucleotide. 3/5 in silico tools predict a damaging outcome for this variant. This variant was found in 30/123662 control chromosomes, predominantly in the East Asian cohort, 29/10878 (0.0027), which does exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). Therefore, suggesting that the variant is a polymorphism found most frequently in population(s) of East Asian origin. In addition, the variant has been reported in 2 unaffected individuals (Carnery_2010), showing evidence for lack of co-segregation. Also multiple clinical diagnostic laboratories/reputable databases classified this variant as likely benign. Taken together, this variant is classified as likely benign.
Mendelics	RCV000045881	SCV000838749	likely benign	Hereditary breast and ovarian cancer syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Mendelics	RCV000031841	SCV001138983	likely benign	Breast-ovarian cancer, familial 2	2019-05-28	criteria provided, single submitter	clinical testing
Illumina Clinical Services Laboratory,Illumina	RCV001109314	SCV001266637	benign	Fanconi anemia, complementation group D1	2017-04-30	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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
Illumina Clinical Services Laboratory,Illumina	RCV000031841	SCV001269209	benign	Breast-ovarian cancer, familial 2	2017-04-30	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 rule this variant out of causing disease. Therefore, this variant is classified as benign.
Research and Development, ARUP Laboratories	RCV001642527	SCV001854657	likely 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
Biesecker Lab/Clinical Genomics Section,National Institutes of Health	RCV000034472	SCV000043193	variant of unknown significance	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Uncertain significance.
Sharing Clinical Reports Project (SCRP)	RCV000031841	SCV000054449	benign	Breast-ovarian cancer, familial 2	2011-03-10	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031841	SCV000145797	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	RCV001353591	SCV000591722	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The p.Lys322Gln variant was identified in 7 of 5142 proband chromosomes from individuals with breast cancer, ovarian cancer, or hepatocellular carcinoma, and was absent in 88 control chromosomes (Borg 2010, Carney 2010, Katagiri 1996, Sugano 2008); however, an insufficient number of controls were included in these studies to determine the frequency of this variant in the general population. The variant was also identified in dbSNP (ID: rs11571640) “With unknown allele”, HGMD, and the BIC database (11X with unknown clinical importance). The variant was listed in 1000 Genomes Project with a frequency of 0.001, and the Japanese HapMap-JPT cohort with frequency of 0.006, increasing the likelihood that this may be a low frequency benign variant in certain populations of origin. This residue is conserved in mammals; however, computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM) provide inconsistent predictions regarding the impact to the protein and this information is not very predictive of pathogenicity. One study predicted this variant to have no effect on cancer risk; however, this was limited to an in silico analysis (Capanu 2011). 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.