rs397507846

Variant names:

• chr13-32340717-A-G
• rs397507846
• NM_000059.4:c.6362A>G

Your query was ambiguous. Multiple possible variants found:

• chr13-32340717-A-G
• chr13-32340717-A-T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_000059.4(BRCA2):​c.6362A>G​(p.Glu2121Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,454,786 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. E2121D) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:7
• Conservation: PhyloP100: 1.91
• Publications: 7 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 -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24686188).
• BP6: Variant 13-32340717-A-G is Benign according to our data. Variant chr13-32340717-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 52074.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000059.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA2	NM_000059.4	MANE Select	c.6362A>G	p.Glu2121Gly	missense	Exon 11 of 27	NP_000050.3
	BRCA2	NM_001432077.1		c.6362A>G	p.Glu2121Gly	missense	Exon 11 of 27	NP_001419006.1
	BRCA2	NM_001406720.1		c.6362A>G	p.Glu2121Gly	missense	Exon 11 of 27	NP_001393649.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA2	ENST00000380152.8	TSL:5 MANE Select	c.6362A>G	p.Glu2121Gly	missense	Exon 11 of 27	ENSP00000369497.3
	BRCA2	ENST00000544455.6	TSL:1	c.6362A>G	p.Glu2121Gly	missense	Exon 11 of 27	ENSP00000439902.1
	BRCA2	ENST00000530893.7	TSL:1	c.5993A>G	p.Glu1998Gly	missense	Exon 11 of 27	ENSP00000499438.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1454786 Hom.: 0 Cov.: 45 AF XY: 0.00000276 AC XY: 2 AN XY: 723466

African (AFR) AF: 0.00 AC: 0 AN: 32914

American (AMR) AF: 0.00 AC: 0 AN: 42734

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25856

East Asian (EAS) AF: 0.00 AC: 0 AN: 39606

South Asian (SAS) AF: 0.00 AC: 0 AN: 84200

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53240

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5716

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1110462

Other (OTH) AF: 0.00 AC: 0 AN: 60058

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000427 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Feb 05, 2024

All of Us Research Program, National Institutes of Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

May 31, 2012

Sharing Clinical Reports Project (SCRP)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

not specified Uncertain:1 Benign:1

Jun 16, 2017

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Aug 27, 2024

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.6362A>G (p.Glu2121Gly) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.9e-06 in 1607146 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.6362A>G has been reported in the literature in individuals undergoing genetic testing for BRCA1/2, without strong evidence for causality and in at least one case it was reported as likely benign due to lack of segregation, however no further details were provided for this family (e.g. Sinilnikova_2006, Coulet_2010, Maxwell_2016). These report(s) do 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 publications have been ascertained in the context of this evaluation (PMID: 20858050, 27153395, 16528604). ClinVar contains an entry for this variant (Variation ID: 52074). Based on the evidence outlined above, the variant was classified as uncertain significance.

Hereditary cancer-predisposing syndrome Benign:2

Apr 02, 2018

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 11, 2018

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.

not provided Uncertain:1

Sep 13, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BRCA2 c.6362A>G (p.Glu2121Gly) variant has been reported in the published literature in a family at high risk for breast and/or ovarian cancer (PMID: 27153395 (2016)). It was detected in the somatic state in a sarcoma/stromal tumor sample (PMID: 34820595 (2021)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). 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.

Malignant tumor of breast Uncertain:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The p.Glu2121Gly variant was not identified in the literature. The variant was identified in HGMD, and in UMD (1X as an unclassified variant). This residue is not conserved in mammals or lower organisms, increasing the likelihood this variant does not have clinical significance. In addition, computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of unknown significance.

Hereditary breast ovarian cancer syndrome Benign:1

Nov 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	0.0058	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	17
DANN	Uncertain	0.99
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.73	D
M_CAP	Uncertain	0.26	D
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-0.88	T
PhyloP100		1.9
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.18
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.031	D
Vest4		0.72
MutPred		0.19		Loss of helix (P = 0.028)
MVP		0.86
MPC		0.039
ClinPred		0.36	T
GERP RS		2.8
gMVP		0.24
Mutation Taster		=86/14	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: rs397507846; hg19: chr13-32914854;