chr13-32319081-A-T

Position:

• chr13-32319081-A-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4

The NM_001406722.1(BRCA2):​c.-298A>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000011 in 1,460,152 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: BRCA2 NM_001406722.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3 O:1
• Conservation: PhyloP100: 2.64

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.

• BP4: Computational evidence support a benign effect (MetaRNN=0.28794175).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.72A>T	p.Leu24Phe	missense_variant	3/27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000530893	c.-298A>T		5_prime_UTR_premature_start_codon_gain_variant	3/27	1		ENSP00000499438.2
BRCA2	ENST00000380152.8	c.72A>T	p.Leu24Phe	missense_variant	3/27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893	c.-298A>T		5_prime_UTR_variant	3/27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.72A>T		non_coding_transcript_exon_variant	2/26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000200 AC: 5 AN: 249982 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135546

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: 0.000231

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000110 AC: 16 AN: 1460152 Hom.: 0 Cov.: 32 AF XY: 0.0000110 AC XY: 8 AN XY: 726450

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: 0.000300

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

BRCA2-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 08, 2023

The BRCA2 c.72A>T variant is predicted to result in the amino acid substitution p.Leu24Phe. This variant has been reported in an individual with breast and/or ovarian cancer (Table 2, Kuusisto et al 2011. PubMed ID: 21356067). This variant is reported in 5 of ~250,000 alleles in gnomAD (http://gnomad.broadinstitute.org/variant/13-32893218-A-T). It is interpreted as uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/52303/).At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 08, 2022

The p.L24F variant (also known as c.72A>T), located in coding exon 2 of the BRCA2 gene, results from an A to T substitution at nucleotide position 72. The leucine at codon 24 is replaced by phenylalanine, an amino acid with highly similar properties. This alteration was identified in a high-risk Finnish Hereditary Breast and/or Ovarian Cancer family (Kuusisto KM et al. Breast Cancer Res, 2011 Feb;13:R20). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Hereditary breast ovarian cancer syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 20, 2022

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. This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 24 of the BRCA2 protein (p.Leu24Phe). This variant is present in population databases (rs397507909, gnomAD 0.02%). This missense change has been observed in individual(s) with breast cancer (PMID: 21356067). ClinVar contains an entry for this variant (Variation ID: 52303). 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. -

Familial cancer of breast Other:1

not provided, no classification provided

literature only

ClinVar Staff, National Center for Biotechnology Information (NCBI)

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Uncertain	0.049	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	22
DANN	Uncertain	0.99
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.94	D
M_CAP	Benign	0.081	D
MetaRNN	Benign	0.29	T;T
MetaSVM	Benign	-1.2	T
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.0	N;N
REVEL	Benign	0.17
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.0080	D;D
Vest4		0.77
MutPred		0.22		Loss of ubiquitination at K21 (P = 0.0863);Loss of ubiquitination at K21 (P = 0.0863);
MVP		0.90
MPC		0.16
ClinPred		0.61	D
GERP RS		5.7
gMVP		0.60

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: rs397507909; hg19: chr13-32893218;