rs1555284585

Positions:

• chr13-32340536-G-A
• chr13-32340536-G-C
• chr13-32340536-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM1 PP3

The NM_000059.4(BRCA2):​c.6181G>A​(p.Ala2061Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,460,808 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:1
• Conservation: PhyloP100: 7.78

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 3 ACMG points.

• PM1: In a repeat BRCA2 8 (size 34) in uniprot entity BRCA2_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) in NM_000059.4
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.797

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.6181G>A	p.Ala2061Thr	missense_variant	11/27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.6181G>A	p.Ala2061Thr	missense_variant	11/27	5	NM_000059.4	ENSP00000369497	A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1460808 Hom.: 0 Cov.: 46 AF XY: 0.00000688 AC XY: 5 AN XY: 726680

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: 0.00000450

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 30, 2021	The p.A2061T variant (also known as c.6181G>A), located in coding exon 10 of the BRCA2 gene, results from a G to A substitution at nucleotide position 6181. The alanine at codon 2061 is replaced by threonine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 15, 2023	This missense variant replaces alanine with threonine at codon 2061 of the BRCA2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in a multifactorial analysis with co-occurrence and family history likelihood ratios for pathogenicity of 1.076 and 0.786, respectively (PMID: 31131967). 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. -
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). -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Dec 18, 2017

Variant summary:The BRCA2 c.6181G>A (p.Ala2061Thr) variant involves the alteration of a conserved nucleotide, is predicted to be damaging by 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index) and is located in BRCA2 repeat 8 which is critical for RAD51 binding (InterPro). This variant is absent in 245114 control chromosomes (gnomAD). The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories, nor has it been evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jun 05, 2024

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; Also known as 6409G>A; This variant is associated with the following publications: (PMID: 31131967, 9002670, 22193408) -

Hereditary breast ovarian cancer syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 26, 2023

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 2061 of the BRCA2 protein (p.Ala2061Thr). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 462399). 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. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	27
DANN	Pathogenic	1.0
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.80	D;D
MetaSVM	Uncertain	0.70	D
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-3.4	D;D
REVEL	Pathogenic	0.80
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0070	D;D
Vest4		0.58
MutPred		0.76		Gain of relative solvent accessibility (P = 0.0023);Gain of relative solvent accessibility (P = 0.0023);
MVP		0.97
MPC		0.16
ClinPred		0.98	D
GERP RS		5.8
gMVP		0.66

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: rs1555284585; hg19: chr13-32914673;