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

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000044656	SCV000072669	benign	Hereditary breast and ovarian cancer syndrome	2020-11-14	criteria provided, single submitter	clinical testing
GeneDx	RCV000590661	SCV000108625	uncertain significance	not provided	2021-08-11	criteria provided, single submitter	clinical testing	Observed in individuals with breast or ovarian cancer (Soegaard 2008, Pal 2015, Encinas 2018); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis supports a deleterious effect on splicing; Also known as 5642A>G; This variant is associated with the following publications: (PMID: 33643918, 33868589, 31256854, 29854292, 26287763, 10923033, 19139070, 27527004, 11929857, 18559594, 9971877)
Ambry Genetics	RCV000131487	SCV000186475	uncertain significance	Hereditary cancer-predisposing syndrome	2020-08-31	criteria provided, single submitter	clinical testing	The p.N1805S variant (also known as c.5414A>G), located in coding exon 10 of the BRCA2 gene, results from an A to G substitution at nucleotide position 5414. The asparagine at codon 1805 is replaced by serine, an amino acid with highly similar properties. This alteration was reported in one control allele in an individual of African descent from a cohort including 332 globally heterogeneous chromosomes (Wagner TM et al. Hum. Mol. Genet. 1999 Mar;8:413-23). This alteration was reported in a cohort of patients diagnosed with early-onset breast cancer and self-reported to have African American and/or Afro-Caribbean, and/or other/mixed descent; the authors classified this alteration as "suspected benign" (Pal T et al. Cancer. 2015 Dec;121:4173-80). This alteration was also reported in 1 of 445 individuals with invasive epithelial ovarian cancer from Denmark (Soegaard M et al. Clin. Cancer Res. 2008 Jun;14:3761-7) as well as two individuals with breast cancer from Brazil (Encinas G et al. Oncotarget. 2018 Apr;9:22460-22479). Of note, this alteration is also designated as 5642A>G in published literature. 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.
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
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000855580	SCV000694867	likely benign	not specified	2021-05-27	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 7.8e-05 in 395988 control chromosomes, predominantly at a frequency of 0.00035 within the African or African-American subpopulation in the gnomAD database (v2.1 and v3.2 dataset). This frequency is somewhat lower than the maximum expected for a pathogenic variant in BRCA2 causing Hereditary Breast and Ovarian Cancer Syndrome (0.00075), allowing no clear conclusions about variant significance. However, the variant was also reported from the southern part of Africa with even higher allele frequencies, e.g. 0.014 (3/208 alleles; in the GenomeAsia 100K database) and 0.027 (Oosthuizen_2021), supporting a benign role for the variant. c.5414A>G has been reported in the literature in individuals affected with breast- and/or ovarian cancer (e.g. Soegaard_2008, Pal_2015, Encinas_2018), but was also found in controls (Wagner_1999). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as Benign (n=1), likely benign (n=2) or VUS (n=6). Based on the evidence outlined above, the variant was classified as likely benign.
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	2020-01-24	criteria provided, single submitter	clinical testing
Color Health, Inc	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
Department of Pathology and Laboratory Medicine,Sinai Health System	RCV001358175	SCV001553846	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2 p.Asn1805Ser variant was identified in 3 of 1982 proband chromosomes (frequency: 0.002) from individuals or families with hereditary breast and ovarian cancer syndrome and was present in 1 of 190 control chromosomes (frequency: 0.005) from healthy individuals (Pal 2015, Soegaard 2008, Wagner 1999, Encinas 2018). The variant was also identified in dbSNP (ID: rs80358765) as "with uncertain significance allele", ClinVar (classified as uncertain significance by Ambry Genetics, GeneDx and six other submitters; and as likely benign by Invitae and Color), and the LOVD 3.0 database. The variant was not identified in UMD-LSDB database. It was also identified in control databases in 18 of 276966 chromosomes at a frequency of 0.00007 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 9 of 24018 chromosomes (freq: 0.0004), Other in 1 of 6456 chromosomes (freq: 0.0002), European in 2 of 126516 chromosomes (freq: 0.00002), and South Asian in 6 of 30774 chromosomes (freq: 0.0002), while the variant was not observed in the Latino, Ashkenazi Jewish, East Asian or Finnish populations. The p.Asn1805Ser residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and three out of four in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, Human Splicing Finder) predict a greater than 10% difference in splicing. 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 uncertain significance.