Submissions for variant NM_000059.4(BRCA2):c.1211A>G (p.Asn404Ser)

dbSNP: rs80358414

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory of Molecular Diagnosis of Cancer, West China Hospital, Sichuan University	RCV000240794	SCV000265929	uncertain significance	Breast neoplasm	2015-11-01	criteria provided, single submitter	research
Labcorp Genetics (formerly Invitae), Labcorp	RCV000472702	SCV000549879	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-10-30	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 404 of the BRCA2 protein (p.Asn404Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer or acute pancreatitis (PMID: 27257965, 35171259, 35264596). ClinVar contains an entry for this variant (Variation ID: 224455). 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.
Ambry Genetics	RCV000571012	SCV000668740	uncertain significance	Hereditary cancer-predisposing syndrome	2021-05-13	criteria provided, single submitter	clinical testing	The p.N404S variant (also known as c.1211A>G), located in coding exon 9 of the BRCA2 gene, results from an A to G substitution at nucleotide position 1211. The asparagine at codon 404 is replaced by serine, an amino acid with highly similar properties. This alteration was identified in 2/507 unselected Chinese breast cancer patients (Zhong X et al. PLoS One, 2016 Jun;11:e0156789). 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.
Color Diagnostics, LLC DBA Color Health	RCV000571012	SCV000683406	uncertain significance	Hereditary cancer-predisposing syndrome	2022-08-15	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with serine at codon 404 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 been detected in two individuals affected with breast cancer (PMID: 27257965). This variant has not been identified 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000586358	SCV000694521	uncertain significance	not provided	2017-05-26	criteria provided, single submitter	clinical testing	Variant summary: The BRCA2 c.1211A>G (p.Asn404Ser) variant involves the alteration of a conserved nucleotide. 4/5 in silico tools predict a benign outcome for this variant. This variant is absent in 120776 control chromosomes. This variant has been detected twice in a cohort of 507 Chinese breast cancer patients without strong evidence for causality. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, due to lack of clinical and functional evidence, this variant is currently classified as VUS.
Mendelics	RCV000988998	SCV001138992	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2019-05-28	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000571012	SCV003849911	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).
PreventionGenetics, part of Exact Sciences	RCV004530255	SCV004113042	uncertain significance	BRCA2-related disorder	2022-11-20	criteria provided, single submitter	clinical testing	The BRCA2 c.1211A>G variant is predicted to result in the amino acid substitution p.Asn404Ser. This variant has been reported as a variant of uncertain significance in multiple individuals with breast and/or ovarian cancer (Table S5 - Bhaskaran et al. 2019. PubMed ID: 30702160; Table S1 - Gao et al. 2019. PubMed ID: 31825140). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. In ClinVar, this variant has been interpreted as uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/224455/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
All of Us Research Program, National Institutes of Health	RCV000988998	SCV004846879	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-03-28	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with serine at codon 404 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 been detected in two individuals affected with breast cancer (PMID: 27257965). This variant has not been identified 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.