Submissions for variant NM_000059.4(BRCA2):c.1211A>T (p.Asn404Ile)

dbSNP: rs80358414

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000588048	SCV000694522	uncertain significance	not provided	2017-06-06	criteria provided, single submitter	clinical testing	Variant summary: The BRCA2 c.1211A>T (p.Asn404Ile) variant involves the alteration of a conserved nucleotide and 3/5 in silico tools predict a damaging outcome for this variant. However, these predictions have yet to be functionally assessed. This variant was found in 1/120776 control chromosomes at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). In addition, one clinical diagnostic laboratory and a reputable database classified this variant as uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications; nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a "Variant of Uncertain Significance (VUS)," until additional information becomes available.
Color Diagnostics, LLC DBA Color Health	RCV000773258	SCV000906883	uncertain significance	Hereditary cancer-predisposing syndrome	2019-06-27	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000773258	SCV001170519	uncertain significance	Hereditary cancer-predisposing syndrome	2022-04-29	criteria provided, single submitter	clinical testing	The p.N404I variant (also known as c.1211A>T), located in coding exon 9 of the BRCA2 gene, results from an A to T substitution at nucleotide position 1211. The asparagine at codon 404 is replaced by isoleucine, an amino acid with dissimilar properties. This alteration has been identified in one Chinese individual diagnosed with breast cancer (Li G et al. J. Cancer Res. Clin. Oncol. 2017 Oct;143:2011-2024). This amino acid position is not well 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001302330	SCV001491534	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-03-13	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 404 of the BRCA2 protein (p.Asn404Ile). This variant is present in population databases (rs80358414, gnomAD 0.003%). This missense change has been observed in individual(s) with breast cancer (PMID: 28664449). ClinVar contains an entry for this variant (Variation ID: 51082). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA2 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000773258	SCV003849910	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).
All of Us Research Program, National Institutes of Health	RCV004803136	SCV005424281	uncertain significance	BRCA2-related cancer predisposition	2024-06-11	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000112892	SCV000145831	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000588048	SCV001550793	uncertain significance	not provided		no assertion criteria provided	clinical testing	The BRCA2 p.Asn404Ile variant was not identified in the literature nor was it identified in the GeneInsight-COGR, Cosmic, MutDB, LOVD 3.0, UMD-LSDB, ARUP Laboratories, or Zhejiang Colon Cancer Database. The variant was identified in dbSNP (ID: rs80358414) “With Uncertain significance allele”, ClinVar (classified uncertain significance by BIC, and classification not provided by Invitae), Clinvitae (1x), BIC Database (1x, clinical importance unknown, classification pending), and in control databases in 1 of 245688 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include Latino in 1 of 33524 chromosomes (freq: 0.00003), while not observed in the African, Other, European Non-Finnish, Ashkenazi Jewish, East Asian, European Finnish, and South Asian populations. The p.Asn404 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the variant Ile impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a 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.