chr13-32338728-A-G

Position:

• chr13-32338728-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000059.4(BRCA2):​c.4373A>G​(p.His1458Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H1458Y) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:1
• Conservation: PhyloP100: -0.201

Genes affected

BRCA2 (HGNC:1101): (BRCA2 DNA repair associated) Inherited mutations in BRCA1 and this gene, BRCA2, confer increased lifetime risk of developing breast or ovarian cancer. Both BRCA1 and BRCA2 are involved in maintenance of genome stability, specifically the homologous recombination pathway for double-strand DNA repair. The largest exon in both genes is exon 11, which harbors the most important and frequent mutations in breast cancer patients. The BRCA2 gene was found on chromosome 13q12.3 in human. The BRCA2 protein contains several copies of a 70 aa motif called the BRC motif, and these motifs mediate binding to the RAD51 recombinase which functions in DNA repair. BRCA2 is considered a tumor suppressor gene, as tumors with BRCA2 mutations generally exhibit loss of heterozygosity (LOH) of the wild-type allele. [provided by RefSeq, May 2020]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10958648).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.4373A>G	p.His1458Arg	missense_variant	11/27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.4373A>G	p.His1458Arg	missense_variant	11/27	5	NM_000059.4	ENSP00000369497	A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Jan 19, 2010	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Dec 04, 2015	- -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 18, 2020	The BRCA2 c.4373A>G; p.His1458Arg variant (rs587782185) is reported in the literature in an individual affected with prostate cancer (Hayano 2016). This variant is also reported in ClinVar (Variation ID: 142023), and is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. The histidine at codon 1458 is weakly conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.236). Due to limited information, the clinical significance of the p.His1458Arg variant is uncertain at this time. References: Hayano T et al. Germline Variants of Prostate Cancer in Japanese Families. PLoS One. 2016 Oct 4;11(10):e0164233. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 11, 2022	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with prostate cancer (Hayano et al., 2016); Also known as 4601A>G; This variant is associated with the following publications: (PMID: 27701467) -

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 05, 2023	The p.H1458R variant (also known as c.4373A>G), located in coding exon 10 of the BRCA2 gene, results from an A to G substitution at nucleotide position 4373. The histidine at codon 1458 is replaced by arginine, an amino acid with highly similar properties. In one study of 140 Japanese prostate cancer patients from 66 families, this alteration was observed in one proband (Hayano T et al. PLoS ONE. 2016 Oct;11:e0164233). 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. -
Likely benign, criteria provided, single submitter	curation	University of Washington Department of Laboratory Medicine, University of Washington	Mar 23, 2023	Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673). -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Feb 27, 2023

Variant summary: BRCA2 c.4373A>G (p.His1458Arg) 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 was absent in 244556 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4373A>G has been reported in the literature in at-least one individual from a small family with pairs of patients affected with prostate cancer where it was not reported to co-segregate with disease (example, Hayano_2016). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five 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. -

Hereditary breast ovarian cancer syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 25, 2023

This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 1458 of the BRCA2 protein (p.His1458Arg). This variant is present in population databases (rs587782185, gnomAD 0.01%). This missense change has been observed in individual(s) with prostate cancer (PMID: 27701467). ClinVar contains an entry for this variant (Variation ID: 142023). 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. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	7.0
DANN	Benign	0.90
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.093	N
M_CAP	Benign	0.047	D
MetaRNN	Benign	0.11	T;T
MetaSVM	Benign	-0.91	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.3	N;N
REVEL	Benign	0.24
Sift	Uncertain	0.0090	D;D
Sift4G	Benign	0.29	T;T
Vest4		0.31
MutPred		0.14		Gain of phosphorylation at S1461 (P = 0.071);Gain of phosphorylation at S1461 (P = 0.071);
MVP		0.73
MPC		0.021
ClinPred		0.21	T
GERP RS		-7.1
gMVP		0.12

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs587782185; hg19: chr13-32912865;