Submissions for variant NM_000059.4(BRCA2):c.5634C>G (p.Asn1878Lys)

gnomAD frequency: 0.00003  dbSNP: rs80358784

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031564	SCV001161520	benign	Breast-ovarian cancer, familial, susceptibility to, 2	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 = 0.000455
Invitae	RCV001084469	SCV000072714	likely benign	Hereditary breast ovarian cancer syndrome	2023-12-30	criteria provided, single submitter	clinical testing
GeneDx	RCV000168579	SCV000210615	likely benign	not specified	2017-02-10	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.
Ambry Genetics	RCV000164012	SCV000214617	likely benign	Hereditary cancer-predisposing syndrome	2018-08-24	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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	RCV000031564	SCV000488757	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2016-06-14	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000195372	SCV000600650	likely benign	not provided	2022-12-08	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000164012	SCV000683718	likely benign	Hereditary cancer-predisposing syndrome	2015-11-24	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000168579	SCV000916942	likely benign	not specified	2020-07-13	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.5634C>G (p.Asn1878Lys) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 248658 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.5634C>G, has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer Syndrome and related tumor phenotypes (e.g. Borg 2010, Balia 2011, Lu 2012, Wong-Brown 2015, Dudley_2018). These reports however do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer Syndrome. Two functional studies from the same group utilizing homologous recombination assays to evaluate an impact on protein function, provided conflicting results about the variant (Spugnesi_2013, Balia_2011). However, a recent multifactorial likelihood analysis predicted this variant to be Benign (Parsons_2019). Nine other submitters, including an expert panel (ENIGMA), have provided clinical-significance assessments for this variant in ClinVar after 2014 without evidence for independent evaluation, and classified the variant as VUS (3x) or likely benign (5x), while the expert panel called the variant benign. Based on the evidence outlined above, the variant was classified as likely benign.
Mendelics	RCV000031564	SCV001139118	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2019-05-28	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000195372	SCV001148987	likely benign	not provided	2022-04-01	criteria provided, single submitter	clinical testing	BRCA2: BP1, BP4, BS2
Sema4, Sema4	RCV000164012	SCV002536153	uncertain significance	Hereditary cancer-predisposing syndrome	2021-09-08	criteria provided, single submitter	curation
PreventionGenetics, part of Exact Sciences	RCV003914883	SCV004734671	likely benign	BRCA2-related condition	2023-08-31	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Sharing Clinical Reports Project (SCRP)	RCV000031564	SCV000054169	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2012-05-01	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031564	SCV000146648	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2004-02-20	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353709	SCV000591980	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2 p.Asn1878Lys variant was identified in 3 of 4892 proband chromosomes (frequency: 0.001) from individuals with case of breast cancer (Balia 2011, Capanu 2011). The variant was reported in dbSNP(ID: rs80358784) “With unknown allele”; however, the only frequency information available was from the “ClinSeq project” where the variant was found in one out of 662 participants (allele frequency: 0.001). The variant was identified eight times in UMD as an unclassified variant, and was also reported in the LOVD and HGMD databases. The p.Asn1878 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD) do not suggest a high likelihood of impact of the variant amino acid (Lys) to the protein. However, this information is not predictive enough to rule out pathogenicity. Loss of heterozygosity analysis of tumours from patients with the variant noted an absence of loss of heterozygosity in one study (Balia 2011); however, in another study the variant allele was lost, providing evidence for neutrality (Spearman 2008). Two assays evaluating homologous recombination activity of the variant yielded conflicting results. In a yeast-based assay, Spugnesi (2013) suggests that the variant may not be deleterious as it conferred a phenotype similar to wildtype. However, in a HeLa cell-based assay, the variant had a level of spontaneous homologous recombination similar to a known deleterious mutation, suggesting that the variant may be pathogenic (Balia 2011). Segregation and/or additional functional studies are recommended to further elucidate the pathogenicity of this variant. 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	RCV000735567	SCV000863705	uncertain significance	Breast and/or ovarian cancer	2013-07-19	no assertion criteria provided	clinical testing