Submissions for variant NM_000059.4(BRCA2):c.5465A>T (p.Asn1822Ile)

dbSNP: rs587781580

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129617	SCV000184410	uncertain significance	Hereditary cancer-predisposing syndrome	2024-07-29	criteria provided, single submitter	clinical testing	The p.N1822I variant (also known as c.5465A>T), located in coding exon 10 of the BRCA2 gene, results from an A to T substitution at nucleotide position 5465. The asparagine at codon 1822 is replaced by isoleucine, an amino acid with dissimilar properties. This variant was detected in 3/143 with breast cancer and 1/382 with ovarian cancer from Peru (Ferreyra Y et al. Front Oncol, 2023 Aug;13:1227864). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000199798	SCV000254193	uncertain significance	Hereditary breast ovarian cancer syndrome	2025-01-20	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 1822 of the BRCA2 protein (p.Asn1822Ile). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 141212). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001375483	SCV000694872	uncertain significance	not specified	2021-04-05	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.5465A>T (p.Asn1822Ile) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251078 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.5465A>T in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000129617	SCV001734885	uncertain significance	Hereditary cancer-predisposing syndrome	2021-07-28	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with isoleucine at codon 1822 of the BRCA2 protein. 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 not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/251078 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000129617	SCV003848833	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).
Myriad Genetics, Inc.	RCV003315878	SCV004019225	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2023-03-31	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
All of Us Research Program, National Institutes of Health	RCV004804133	SCV005424482	uncertain significance	BRCA2-related cancer predisposition	2024-08-29	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with isoleucine at codon 1822 of the BRCA2 protein. 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 not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/251078 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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000588979	SCV000591970	uncertain significance	not provided		no assertion criteria provided	clinical testing	The p.Asn1822Ile variant has not been previously reported in the literature. The p.Asn1822 residue is not conserved across mammals increasing the likelihood a change to this residue does not have clinical significance. However, computational analyses (PolyPhen, SIFT, AlignGVGD) suggest that the p.Asn1822Ile variant may impact the protein but this information is not predictive enough to assume pathogenicity. 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 unknown significance.
Department of Medical and Surgical Sciences, University of Bologna	RCV003315878	SCV004228411	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2023-09-01	no assertion criteria provided	clinical testing	PM2(Supporting)+BP1(Strong) according to ACMG/AMP classification guidelines specified for BRCA1 & BRCA2 (Classification Criteria V1.0.0 2023-09-08 - https://cspec.genome.network/cspec/ui/svi/affiliation/50087) (PMID: 38160042)