rs368952892

chr13-32339096-G-Achr13-32339096-G-Cchr13-32339096-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM2 PM5 BP4 BP6

The NM_000059.4(BRCA2):c.4741G>A(p.Glu1581Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 152,136 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 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. E1581K?) has been classified as Pathogenic.

• Frequency: Genomes: 𝑓 0.000013 (0 hom., cov: 33)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9 B:2
• Conservation: PhyloP100: 2.98

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr13-32339096-G-AA is described in ClinVar as [Pathogenic]. Clinvar id is 266830.Status of the report is reviewed_by_expert_panel, 3 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.29901913).
• BP6: Variant 13-32339096-G-A is Benign according to our data. Variant chr13-32339096-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 37920.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=8, Likely_benign=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4	c.4741G>A	p.Glu1581Lys	missense_variant	11/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.4741G>A	p.Glu1581Lys	missense_variant	11/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152136 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00000797 AC: 2 AN: 251010 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135748

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.000163

GnomAD4 exome Cov.: 46

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152136 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74314

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000478

Bravo AF: 0.00000756

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:9 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:5

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Mar 19, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Michigan Medical Genetics Laboratories, University of Michigan	Apr 21, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Oct 30, 2023	This missense variant replaces glutamic acid with lysine at codon 1581 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 3/282414 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Mar 23, 2018	- -
Uncertain significance, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Aug 12, 2008	- -

Hereditary cancer-predisposing syndrome Uncertain:3 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 14, 2023	The p.E1581K variant (also known as c.4741G>A), located in coding exon 10 of the BRCA2 gene, results from a G to A substitution at nucleotide position 4741. The glutamic acid at codon 1581 is replaced by lysine, an amino acid with similar properties. 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. -
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). -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Jan 16, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jul 19, 2021	This missense variant replaces glutamic acid with lysine at codon 1581 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 3/282414 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. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Mar 29, 2024

Variant summary: BRCA2 c.4741G>A (p.Glu1581Lys) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251010 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.4741G>A in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 37920). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

Hereditary breast ovarian cancer syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 08, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.073	T
BayesDel_noAF	Benign	-0.34
Cadd	Benign	15
Dann	Benign	0.97
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.48
FATHMM_MKL	Uncertain	0.83	D
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.30	T;T
MetaSVM	Benign	-0.94	T
MutationTaster	Benign	0.93	N;N
PrimateAI	Benign	0.34	T
PROVEAN	Uncertain	-3.1	D;D
REVEL	Benign	0.17
Sift	Benign	0.055	T;T
Sift4G	Benign	0.097	T;T
Vest4		0.41
MVP		0.88
MPC		0.030
ClinPred		0.30	T
GERP RS		4.8
gMVP		0.32

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: rs368952892; hg19: chr13-32913233; COSMIC: COSV66465245;