13-32341140-T-G

Position:

• chr13-32341140-T-G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_Moderate BP6

The NM_000059.4(BRCA2):​c.6785T>G​(p.Met2262Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000149 in 1,613,830 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).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:6
• Conservation: PhyloP100: -1.04

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 -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.08029464).
• BP6: Variant 13-32341140-T-G is Benign according to our data. Variant chr13-32341140-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 52183.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=6, Benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.6785T>G	p.Met2262Arg	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.6785T>G	p.Met2262Arg	missense_variant	11/27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.6416T>G	p.Met2139Arg	missense_variant	11/27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.6785T>G		non_coding_transcript_exon_variant	10/26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152186 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000797 AC: 2 AN: 251098 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135854

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: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000157 AC: 23 AN: 1461644 Hom.: 0 Cov.: 35 AF XY: 0.0000138 AC XY: 10 AN XY: 727130

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: 0.0000162

Gnomad4 OTH exome AF: 0.0000828

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152186 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74344

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:3 Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	Feb 20, 2004	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Dec 27, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Likely benign, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Nov 30, 2012	- -

Hereditary cancer-predisposing syndrome Benign:3

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). -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 18, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 29, 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. -

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 17, 2021	DNA sequence analysis of the BRCA2 gene demonstrated a sequence change, c.6785T>G, in exon 11 that results in an amino acid change, p.Met2262Arg. This sequence change has been described in the gnomAD database with a frequency of 0.0018% in the non-Finnish European subpopulation (dbSNP rs80358904). The p.Met2262Arg change affects a poorly conserved amino acid residue located in a domain of the BRCA2 protein that is known to be functional. The p.Met2262Arg substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This sequence change does not appear to have been previously described in individuals with BRCA2-related disorders, however, a different amino acid change at the same position, p.Met2262Thr, has been reported in an individual with triple negative breast cancer (PMID: 26010302). Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Met2262Arg change remains unknown at this time. -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 12, 2023	Variant summary: BRCA2 c.6785T>G (p.Met2262Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five 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 251098 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.6785T>G has been reported in the literature in at-least one individual with a diagnosis of ovarian cancer, however authors classified the variant as uncertain significance (example: Alsop_2012). This report does not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 22711857). Nine submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS(n=4) and benign/likely benign(n= 5). Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 31, 2019	This variant is associated with the following publications: (PMID: 22711857) -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Dec 02, 2024	The BRCA2 c.6785T>G (p.Met2262Arg) variant has been reported in the published literature in an affected individual with ovarian cancer (PMID: 22711857 (2012)), as well as reportedly healthy individuals (PMID: 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/BRCA2)). It is also described to be located in a region of the BRCA2 gene that is tolerant to missense sequence changes (PMID: 31911673 (2020)). The frequency of this variant in the general population, 0.000008 (2/251098 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. 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. -

Fanconi anemia complementation group D1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Hereditary breast ovarian cancer syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.015	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	0.045
DANN	Benign	0.50
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.037	N
M_CAP	Benign	0.054	D
MetaRNN	Benign	0.080	T;T
MetaSVM	Benign	-0.94	T
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.44	N;N
REVEL	Uncertain	0.42
Sift	Benign	0.49	T;T
Sift4G	Benign	0.45	T;T
Vest4		0.38
MutPred		0.24		Loss of sheet (P = 0.0357);Loss of sheet (P = 0.0357);
MVP		0.67
MPC		0.023
ClinPred		0.031	T
GERP RS		-9.3
gMVP		0.10

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: rs80358904; hg19: chr13-32915277;