chr13-32357808-T-G

Position:

• chr13-32357808-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_000059.4(BRCA2):​c.7684T>G​(p.Phe2562Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 7.45

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]

BRCA2 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.975
• PP5: Variant 13-32357808-T-G is Pathogenic according to our data. Variant chr13-32357808-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 182243.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.7684T>G	p.Phe2562Val	missense_variant	16/27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.7684T>G	p.Phe2562Val	missense_variant	16/27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.7315T>G	p.Phe2439Val	missense_variant	16/27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.7684T>G		non_coding_transcript_exon_variant	15/26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Apr 09, 2021

Published functional studies demonstrate a damaging effect: non-functional in a homology-directed repair assay, sensitive to PARP inhibitors and carboplatin (Ikegami 2020, Richardson 2021); Not observed in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 7912T>G; This variant is associated with the following publications: (PMID: 32444794, 33609447) -

Hereditary breast ovarian cancer syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 26, 2018

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 sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with BRCA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 182243). This variant is not present in population databases (ExAC no frequency). This sequence change replaces phenylalanine with valine at codon 2562 of the BRCA2 protein (p.Phe2562Val). The phenylalanine residue is highly conserved and there is a small physicochemical difference between phenylalanine and valine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	29
DANN	Uncertain	0.99
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.55	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Pathogenic	1.1	D
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-2.1	N;N
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Vest4		0.73
MutPred		0.86		Gain of helix (P = 0.027);Gain of helix (P = 0.027);
MVP		0.98
MPC		0.18
ClinPred		1.0	D
GERP RS		5.2
gMVP		0.79

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.27		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.27		Position offset: 0

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

Publications

LitVar

Other links and lift over

dbSNP: rs80358995; hg19: chr13-32931945;