Submissions for variant NM_000059.3(BRCA2):c.5414A>G (p.Asn1805Ser) (rs80358765)

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000044656	SCV000072669	benign	Hereditary breast and ovarian cancer syndrome	2019-12-31	criteria provided, single submitter	clinical testing
GeneDx	RCV000590661	SCV000108625	uncertain significance	not provided	2018-08-13	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.5414A>G at the cDNA level, p.Asn1805Ser (N1805S) at the protein level, and results in the change of an Asparagine to a Serine (AAT>AGT). Using alternate nomenclature, this variant has been previously published as BRCA2 5642A>G. BRCA2 Asn1805Ser has been reported in several individuals with breast or ovarian cancer as well as in a control patient in a separate study (Wagner 1999, Soegaard 2008, Pal 2015, Encinas 2018). This variant was observed at an allele frequency of 0.038% (9/24,018) in individuals of African ancestry in large population cohorts (Lek 2016). This variant is located in the RAD51 binding domain (Roy 2012). Protein-based in silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. In addition, multiple splicing models predict that this variant may create a cryptic splice donor site. However, in the absence of RNA or functional studies, the actual effect of this variant is unknown. Based on currently available evidence, it is unclear whether BRCA2 Asn1805Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000131487	SCV000186475	uncertain significance	Hereditary cancer-predisposing syndrome	2018-06-27	criteria provided, single submitter	clinical testing	Insufficient or conflicting evidence
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000113427	SCV000296612	uncertain significance	Breast-ovarian cancer, familial 2	2016-03-30	criteria provided, single submitter	clinical testing
Integrated Genetics/Laboratory Corporation of America	RCV000855580	SCV000694867	uncertain significance	not specified	2019-05-23	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.5414A>G (p.Asn1805Ser) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6e-05 in 251368 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in BRCA2 causing Hereditary Breast and Ovarian Cancer (6e-05 vs 0.00075), allowing no conclusion about variant significance. c.5414A>G has been reported in the literature in individuals affected with Breast and Ovarian Cancer as well as in control population (Soegaard_2008, Wagner_1999, Encinas_2018, Pal_2015). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (5x uncertain significance and 2x likely benign). Based on the evidence outlined above, the variant was classified as uncertain significance.
Counsyl	RCV000113427	SCV000784936	uncertain significance	Breast-ovarian cancer, familial 2	2017-02-14	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories	RCV000590661	SCV000885113	uncertain significance	not provided	2017-09-14	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000590661	SCV000889068	likely benign	not provided	2018-11-13	criteria provided, single submitter	clinical testing
Color	RCV000131487	SCV000903212	likely benign	Hereditary cancer-predisposing syndrome	2015-08-14	criteria provided, single submitter	clinical testing
Mendelics	RCV000113427	SCV001139113	uncertain significance	Breast-ovarian cancer, familial 2	2019-05-28	criteria provided, single submitter	clinical testing
Illumina Clinical Services Laboratory,Illumina	RCV000113427	SCV001270128	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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Clinical Services Laboratory,Illumina	RCV001112467	SCV001270129	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.
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113427	SCV000146610	uncertain significance	Breast-ovarian cancer, familial 2	2004-02-20	no assertion criteria provided	clinical testing