chr13-32332848-A-G

Position:

• chr13-32332848-A-G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_000059.4(BRCA2):​c.1370A>G​(p.Lys457Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,544 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).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 0.943

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 Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14783499).
• BP6: Variant 13-32332848-A-G is Benign according to our data. Variant chr13-32332848-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 373828.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.1370A>G	p.Lys457Arg	missense_variant	10/27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.1370A>G	p.Lys457Arg	missense_variant	10/27	5	NM_000059.4	ENSP00000369497	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000403 AC: 1 AN: 248398 Hom.: 0 AF XY: 0.00000745 AC XY: 1 AN XY: 134282

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: 0.0000337

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459544 Hom.: 0 Cov.: 35 AF XY: 0.00000138 AC XY: 1 AN XY: 725874

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000117

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Breast neoplasm Uncertain:1

Uncertain significance, criteria provided, single submitter

research

A.C.Camargo Cancer Center / LGBM, A.C.Camargo Cancer Center

-

- -

Hereditary breast ovarian cancer syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 22, 2019

This sequence change replaces lysine with arginine at codon 457 of the BRCA2 protein (p.Lys457Arg). The lysine residue is weakly conserved and there is a small physicochemical difference between lysine and arginine. This variant is present in population databases (rs771442299, ExAC 0.006%). 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with BRCA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 373828). -

Hereditary cancer-predisposing syndrome Benign:1

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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	17
DANN	Uncertain	1.0
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.52	D
M_CAP	Benign	0.078	D
MetaRNN	Benign	0.15	T;T
MetaSVM	Benign	-0.90	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.69	N;N
REVEL	Benign	0.16
Sift	Uncertain	0.010	D;D
Sift4G	Benign	0.15	T;T
Vest4		0.25
MutPred		0.13		Loss of ubiquitination at K457 (P = 6e-04);Loss of ubiquitination at K457 (P = 6e-04);
MVP		0.83
MPC		0.067
ClinPred		0.44	T
GERP RS		0.66
gMVP		0.070

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: rs771442299; hg19: chr13-32906985;