Submissions for variant NM_000059.4(BRCA2):c.5414A>G (p.Asn1805Ser)

gnomAD frequency: 0.00010  dbSNP: rs80358765

Total submissions: 22

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000044656	SCV000072669	benign	Hereditary breast ovarian cancer syndrome	2025-01-16	criteria provided, single submitter	clinical testing
GeneDx	RCV000590661	SCV000108625	uncertain significance	not provided	2024-03-20	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as 5642A>G; Observed in individuals with breast or ovarian cancer (PMID: 18559594, 26287763, 29854292, 34503154, 37335020, 33471991); This variant is associated with the following publications: (PMID: 29854292, 9971877, 18559594, 11929857, 27527004, 19139070, 10923033, 26287763, 31256854, 33868589, 33643918, 35464868, 34503154, 33471991, 10453741, 37335020)
Ambry Genetics	RCV000131487	SCV000186475	likely benign	Hereditary cancer-predisposing syndrome	2022-09-28	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000855580	SCV000694867	likely benign	not specified	2024-05-09	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 6.4e-05 in 1614022 control chromosomes, predominantly at a frequency of 0.00063 within the African or African-American subpopulation in the gnomAD database (v4.0.0). This frequency is close to the estimated maximum for a pathogenic variant in BRCA2 causing Hereditary Breast And Ovarian Cancer Syndrome (0.00075). 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. The following publications have been ascertained in the context of this evaluation (PMID: 10453741, 11929857, 18559594, 26287763, 29854292, 33643918, 33868589). ClinVar contains an entry for this variant (Variation ID: 51858). Based on the evidence outlined above, the variant was classified as likely benign.
Counsyl	RCV000113427	SCV000784936	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 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	2022-12-03	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	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, susceptibility to, 2	2019-05-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000113427	SCV001270128	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 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 Laboratory Services, 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.
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV000044656	SCV002026117	benign	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000113427	SCV002030107	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2021-06-04	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Sema4, Sema4	RCV000131487	SCV002536135	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-18	criteria provided, single submitter	curation
MGZ Medical Genetics Center	RCV003607214	SCV002580882	likely benign	Familial cancer of breast	2024-02-09	criteria provided, single submitter	clinical testing	ACMG codes applied following ENIGMA VCEP rules: BP1_STR
Revvity Omics, Revvity	RCV000590661	SCV003830137	uncertain significance	not provided	2021-10-20	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000131487	SCV003847228	likely benign	Hereditary cancer-predisposing syndrome	2023-03-23	criteria provided, single submitter	curation	Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000044656	SCV005045407	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-02-14	criteria provided, single submitter	clinical testing
Genomics and Molecular Medicine Service, East Genomic Laboratory Hub, NHS Genomic Medicine Service	RCV004584183	SCV005068374	benign	Inherited breast cancer and ovarian cancer	2024-05-02	criteria provided, single submitter	clinical testing	BS1_Strong,BP1,BP4
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113427	SCV000146610	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	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.
BRCAlab, Lund University	RCV000113427	SCV004243667	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2020-03-02	no assertion criteria provided	clinical testing