13-32398675-A-G

Position:

• chr13-32398675-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.10162A>G​(p.Thr3388Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,854 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. T3388K) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• Conservation: PhyloP100: -0.472

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_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07525998).
• BP6: Variant 13-32398675-A-G is Benign according to our data. Variant chr13-32398675-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 96759.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.10162A>G	p.Thr3388Ala	missense_variant	27/27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.10162A>G	p.Thr3388Ala	missense_variant	27/27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.9793A>G	p.Thr3265Ala	missense_variant	27/27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.*2220A>G		non_coding_transcript_exon_variant	26/26	2		ENSP00000506251.1
BRCA2	ENST00000614259.2	n.*2220A>G		3_prime_UTR_variant	26/26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461854 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727228

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 27, 2019	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jul 07, 2021	This missense variant replaces threonine with alanine at codon 3388 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 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. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Apr 04, 2016

Variant Summary: Variant of interest impacts a non-conserved nucleotide and results in a replacement of a medium size and polar Threonine (T) with a small size and hydrophobic Alanine (A). 3/4 in silico tools predict the variant to be benign, and to our knowledge studies assessing the impact of the variant in isolation on the function of the protein were not published at the time of variant classification. It is absent from the large and broad cohorts of the ExAC project and has not been cited in patients from the literature. However, a nonsense BRCA2 variant located upstream of the variant of interest (p.Lys3326Ter) is a well know benign variant, indicating that Thr3388 is a non-essential amino acid for BRCA2 function, and thus p.Thr3388Ala is likely in the benign spectrum. Moreover, a clinical laboratory classified the variant as Likely benign via ClinVar (without evidence to independently evaluate). Considering all evidence, the variant was classified as a VUS-possibly benign/benign until more information becomes available. -

Breast-ovarian cancer, familial, susceptibility to, 2 Benign:1

Likely benign, no assertion criteria provided

clinical testing

Sharing Clinical Reports Project (SCRP)

May 01, 2012

- -

Hereditary breast ovarian cancer syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 16, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.071
DANN	Benign	0.53
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.015	N
M_CAP	Benign	0.054	D
MetaRNN	Benign	0.075	T;T
MetaSVM	Benign	-0.89	T
PrimateAI	Benign	0.19	T
PROVEAN	Benign	-0.62	N;N
REVEL	Benign	0.058
Sift	Benign	0.44	T;T
Sift4G	Benign	0.28	T;T
Vest4		0.032
MutPred		0.090		Loss of solvent accessibility (P = 0.0533);Loss of solvent accessibility (P = 0.0533);
MVP		0.70
MPC		0.020
ClinPred		0.021	T
GERP RS		-11
gMVP		0.13

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: rs431825278; hg19: chr13-32972812;