Submissions for variant NM_000059.3(BRCA2):c.323A>G (p.Asn108Ser) (rs80358568)

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000166938	SCV000217758	uncertain significance	Hereditary cancer-predisposing syndrome	2019-04-08	criteria provided, single submitter	clinical testing	The p.N108S variant (also known as c.323A>G), located in coding exon 3 of the BRCA2 gene, results from an A to G substitution at nucleotide position 323. The asparagine at codon 108 is replaced by serine, an amino acid with highly similar properties. This alteration has been reported in one patient who was diagnosed with high-grade serous ovarian carcinoma in her 70s without family history of breast or ovarian cancer in any first- or second-degree relatives from a cohort of 158 Brazilian ovarian cancer patients (Cotrim DP et al. BMC Cancer, 2019 Jan;19:4). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV000221445	SCV000279279	uncertain significance	not provided	2018-05-16	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.323A>G at the cDNA level, p.Asn108Ser (N108S) at the protein level, and results in the change of an Asparagine to a Serine (AAT>AGT). Using alternate nomenclature, this variant would be defined as BRCA2 551A>G. This variant was observed in an individual during a validation study of a high-throughput protocol for variant identification; however, no clinical information was provided (Hondow 2011). BRCA2 Asn108Ser was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether BRCA2 Asn108Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Illumina Clinical Services Laboratory,Illumina	RCV000315720	SCV000383610	uncertain significance	Fanconi anemia, complementation group D1	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Clinical Services Laboratory,Illumina	RCV000077298	SCV000383611	uncertain significance	Breast-ovarian cancer, familial 2	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Counsyl	RCV000077298	SCV000488230	uncertain significance	Breast-ovarian cancer, familial 2	2016-02-08	criteria provided, single submitter	clinical testing
Color Health, Inc	RCV000166938	SCV000683538	uncertain significance	Hereditary cancer-predisposing syndrome	2019-04-22	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000077298	SCV000109095	uncertain significance	Breast-ovarian cancer, familial 2	2013-10-07	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000077298	SCV000146593	uncertain significance	Breast-ovarian cancer, familial 2	1998-06-22	no assertion criteria provided	clinical testing