Submissions for variant NM_000059.4(BRCA2):c.5729A>T (p.Asn1910Ile)

gnomAD frequency: 0.00001  dbSNP: rs276174863

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000132401	SCV000187493	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-30	criteria provided, single submitter	clinical testing	The p.N1910I variant (also known as c.5729A>T), located in coding exon 10 of the BRCA2 gene, results from an A to T substitution at nucleotide position 5729. The asparagine at codon 1910 is replaced by isoleucine, an amino acid with dissimilar properties. This alteration has been previously reported in cohorts of individuals with personal and/or family history consistent with hereditary breast and/or ovarian cancer syndrome (HBOC) (Beristain E et al. Breast Cancer Res. Treat. 2007 Dec; 106(2):255-62; Vogel KJ et al. J. Clin. Oncol. 2007 Oct; 25(29):4635-41; Palomba G et al. BMC Cancer, 2009 Jul;9:245; Peixoto A et al. Clin. Genet. 2015 Jul; 88(1):41-8; Castellanos E et al. Sci Rep, 2017 01;7:39348; Guindalini RSC et al. Sci Rep, 2022 Mar;12:4190). 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.
Invitae	RCV000457400	SCV000549623	likely benign	Hereditary breast ovarian cancer syndrome	2023-12-12	criteria provided, single submitter	clinical testing
Mendelics	RCV000457400	SCV000838821	uncertain significance	Hereditary breast ovarian cancer syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Mendelics	RCV000082947	SCV001139125	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2019-05-28	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001283930	SCV001469438	uncertain significance	not provided	2023-06-30	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in individuals/families with breast and/or ovarian cancer (PMIDs: 17262179 (2007), 17925560 (2007), 19619314 (2009), 24916970 (2015), 28651617 (2017), 35264596 (2022)). The frequency of this variant in the general population, 0.000032 (1/31408 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
GeneDx	RCV001283930	SCV002504068	likely benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing	See Variant Classification Assertion Criteria.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000132401	SCV003849055	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).
Color Diagnostics, LLC DBA Color Health	RCV000132401	SCV004362125	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-23	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with isoleucine at codon 1910 of the BRCA2 protein. This variant is also known as 5957A>T in the literature. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals with a personal and/or family history of breast or ovarian cancer (PMID: 24916970, 17262179, 17925560, 19619314). This variant has been identified in 1/31408 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Sharing Clinical Reports Project (SCRP)	RCV000082947	SCV000115021	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2012-05-01	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000082947	SCV000591994	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2		no assertion criteria provided	clinical testing	The p.Asn1910Ile variant has been reported in at least 1/536 probands tested for breast and or ovarian carcinoma, and was absent in 103 controls (Beristain 2010, Vogel 2007, Palomba 2009). In addition, these authors suggest the variant has be classified either as a variant of unknown significance or as a benign variant. This variant has not been identified in over 1500 proband chromosomes tested by our laboratory from individuals of different racial backgrounds, suggesting it is a rare variant. However, we cannot rule out that this is a rare benign variant in a population that our laboratory has not tested. The p.Asn1910 residue is not conserved in mammals and computational analyses (SIFT, AlignGVGD) do not suggest a high likelihood of impact to the protein. However, this information is not predictive enough to rule out pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time, although we would lean towards a more benign role for this variant. However, this variant is classified as a variant of unknown significance.