rs397507393

Variant names:

• chr13-32331021-G-A
• rs397507393
• NM_000059.4:c.784G>A

Your query was ambiguous. Multiple possible variants found:

• chr13-32331021-G-A
• chr13-32331021-G-C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_000059.4(BRCA2):​c.784G>A​(p.Ala262Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000481 in 1,455,064 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 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. A262P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:1
• Conservation: PhyloP100: -0.864
• Publications: 12 publications found

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 Gene-Disease associations (from GenCC):

• breast-ovarian cancer, familial, susceptibility to, 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen
• Fanconi anemia complementation group D1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen, G2P
• pancreatic cancer, susceptibility to, 2

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• sarcoma

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• hereditary breast ovarian cancer syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• medulloblastoma

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.04779744).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.784G>A	p.Ala262Thr	missense_variant	Exon 9 of 27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.784G>A	p.Ala262Thr	missense_variant	Exon 9 of 27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.415G>A	p.Ala139Thr	missense_variant	Exon 9 of 27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.784G>A		non_coding_transcript_exon_variant	Exon 8 of 26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000801 AC: 2 AN: 249784 AF XY: 0.0000148

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000481 AC: 7 AN: 1455064 Hom.: 0 Cov.: 29 AF XY: 0.00000414 AC XY: 3 AN XY: 724258

African (AFR) AF: 0.00 AC: 0 AN: 33312

American (AMR) AF: 0.00 AC: 0 AN: 44654

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26068

East Asian (EAS) AF: 0.00 AC: 0 AN: 39636

South Asian (SAS) AF: 0.0000814 AC: 7 AN: 86028

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53378

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5746

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1106072

Other (OTH) AF: 0.00 AC: 0 AN: 60170

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:1

Dec 15, 2021

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Aug 08, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces alanine with threonine at codon 262 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function. A functional study has reported that this variant may have a partial loss-of-function with mild sensitivity to PARP inhibitor and mislocalization to sites of DNA damage, but no sensitivity to cisplatin, MMC and other DNA damaging agents in Brca2-deficient mouse embryonic stem cells (PMID: 32393398). This variant has been reported in an individual affected with breast and ovarian cancer (PMID: 32393398), and it has been detected in a breast cancer case-control meta-analysis in 1/60466 cases and 1/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_007756). A multifactorial analysis has reported a likelihood ratio based on personal and family history of 0.538 from log(LR)=-0.269334614 (PMID: 31853058). This variant has been identified in 2/249784 chromosomes 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 specified Uncertain:1

Aug 09, 2022

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: BRCA2 c.784G>A (p.Ala262Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 249784 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.784G>A has been reported in the literature in at least one individual affected with Hereditary Breast And Ovarian Cancer Syndrome (e.g. Sirisena_2020). This report does not provide unequivocal conclusions about association of the variant with disease. At least one publication has reported experimental evidence evaluating the variant and found that it had a very mild effect on protein function (e.g. Sirisena_2020). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and both classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

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

Jun 21, 2010

Sharing Clinical Reports Project (SCRP)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

BRCA2-related cancer predisposition Uncertain:1

Aug 23, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces alanine with threonine at codon 262 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function. A functional study has reported that this variant may have a partial loss-of-function with mild sensitivity to PARP inhibitor and mislocalization to sites of DNA damage, but no sensitivity to cisplatin, MMC and other DNA damaging agents in Brca2-deficient mouse embryonic stem cells (PMID: 32393398). This variant has been reported in an individual affected with breast and ovarian cancer (PMID: 32393398), and it has been detected in a breast cancer case-control meta-analysis in 1/60466 cases and 1/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_007756). A multifactorial analysis has reported a likelihood ratio based on personal and family history of 0.538 from log(LR)=-0.269334614 (PMID: 31853058). This variant has been identified in 2/249784 chromosomes 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

Mar 31, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The frequency of this variant in the general population, 0.000008 (2/249784 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in an affected individual with breast and ovarian cancer with a family history of cancer (PMID: 32393398 (2020)), as well as in a breast cancer case and a control individual in a large scale breast cancer association study (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/BRCA2)). A functional study observed a reduction in homologous recombination in a green fluorescent protein (GFP)-based reporter assay as compared to wild type (PMID: 32393398 (2020)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. -

Hereditary breast ovarian cancer syndrome Uncertain:1

Oct 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 262 of the BRCA2 protein (p.Ala262Thr). This variant is present in population databases (rs397507393, gnomAD 0.007%). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 32393398). ClinVar contains an entry for this variant (Variation ID: 38121). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt BRCA2 protein function with a negative predictive value of 95%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on BRCA2 function (PMID: 32393398). 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	Benign	0.063
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	0.17
DANN	Benign	0.21
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0027	N
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.048	T;T
MetaSVM	Benign	-0.93	T
PhyloP100		-0.86
PrimateAI	Benign	0.23	T
PROVEAN	Benign	0.39	N;N
REVEL	Uncertain	0.45
Sift	Benign	0.68	T;T
Sift4G	Benign	0.76	T;T
Vest4		0.15
MutPred		0.11		Gain of phosphorylation at A262 (P = 0.0829);Gain of phosphorylation at A262 (P = 0.0829);
MVP		0.71
MPC		0.020
ClinPred		0.012	T
GERP RS		-2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
gMVP		0.095
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs397507393; hg19: chr13-32905158;