rs56403624

Positions:

• chr13-32332863-A-G
• chr13-32332863-A-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Moderate BP6_Very_Strong

The NM_000059.4(BRCA2):​c.1385A>G​(p.Glu462Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000246 in 1,611,804 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E462D) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00025 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Benign reviewed by expert panel U:2 B:24
• Conservation: PhyloP100: 1.22

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 Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.12106818).
• BP6: Variant 13-32332863-A-G is Benign according to our data. Variant chr13-32332863-A-G is described in ClinVar as [Benign]. Clinvar id is 37738.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32332863-A-G is described in Lovd as [Benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4	c.1385A>G	p.Glu462Gly	missense_variant	10/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.1385A>G	p.Glu462Gly	missense_variant	10/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes AF: 0.000184 AC: 28 AN: 152256 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000723

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: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000246 AC: 61 AN: 248384 Hom.: 0 AF XY: 0.000275 AC XY: 37 AN XY: 134302

Gnomad AFR exome AF: 0.0000621

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: 0.000278

Gnomad NFE exome AF: 0.000479

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000252 AC: 368 AN: 1459548 Hom.: 0 Cov.: 35 AF XY: 0.000251 AC XY: 182 AN XY: 725902

Gnomad4 AFR exome AF: 0.0000300

Gnomad4 AMR exome AF: 0.0000226

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000469

Gnomad4 FIN exome AF: 0.000187

Gnomad4 NFE exome AF: 0.000302

Gnomad4 OTH exome AF: 0.000216

GnomAD4 genome AF: 0.000184 AC: 28 AN: 152256 Hom.: 0 Cov.: 32 AF XY: 0.000202 AC XY: 15 AN XY: 74390

Gnomad4 AFR AF: 0.0000723

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000353

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000345 Hom.: 0

Bravo AF: 0.000162

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000239 AC: 29

EpiCase AF: 0.000327

EpiControl AF: 0.000415

ClinVar

Significance: Benign

Submissions summary: Uncertain:2 Benign:24

Revision: reviewed by expert panel

Submissions by phenotype

not specified Uncertain:1 Benign:8

Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 13, 2014	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Multiple publications classify as VUS/not pathogenic; ExAC: 27/66408 European chromosomes -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The BRCA2 p.Glu462Gly variant was identified in 16 of 5462 proband chromosomes (frequency: 0.003) from individuals with breast or ovarian cancer and was absent in 200 control chromosomes from theses studies (Capanu 2011, Farrugia 2008, Hadjisavvas 2003, Hadjisavvas 2004, Simard 2007, van Harssel 2010); however, an insufficient number of controls were included in these studies to determine the frequency of this variant in the general population. The variant was also reported in HGMD, LOVD, UMD (14X as a neutral variant), and the BIC database (37X with unknown clinical importance). This variant was identified in dbSNP (ID: rs56403624) “With non-pathogenic allele”, and at a low frequency (0.0003) in the NHLBI Exome Sequencing Project. This residue is conserved in mammals but not in lower organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. Functional assays assessing cell survival, homologous recombination, centrosome regulation and nuclear localization have found no effect of the variant on normal BRCA2 function (Farrugia 2008, Wu 2005). In addition, five in silico studies predict this variant to be neutral or of little clinical significance (Capanu 2011 21520273, Easton 2007, Farrugia 2008, Lindor 2012, van Harssel 2010). This variant was not found to co-segregate with disease in an assessment of four families (Mohammadi 2009), and Simard (2007) found this variant co-occurring with a known deleterious mutation, increasing the likelihood that this variant does not have functional importance. Furthermore, Myriad classifies this variant as a polymorphism (personal communication). In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign. -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 16, 2021	DNA sequence analysis of the BRCA2 gene demonstrated a sequence change, c.1385A>G, in exon 10 that results in an amino acid change, p.Glu462Gly. This sequence change has been described in the gnomAD database with a frequency of 0.043% in the European sub-population (dbSNP rs56403624). The p.Glu462Gly change was reported to co-occur with a pathogenic sequence change in the BRCA2 gene (PMID: 16905680). In addition, this variant was found not to segregate with disease in affected families (PMID: 19200354). The p. Glu462Gly change affects a moderately conserved amino acid residue located in a domain of the BRCA2 protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Glu462Gly change. Functional studies reported that this sequence change demonstrates similar protein function to the wild-type allele in assays of cellular survival and viability, homologous recombination repair and genome stability (PMID: 15695382). These collective evidences indicate that this is a likely benign sequence change. -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:1 Benign:7

Benign, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Sep 07, 2006	- -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	May 29, 2002	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -
Benign, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Aug 10, 2015	IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.00000293 -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Benign, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Mar 02, 2020	- -
Likely benign, criteria provided, single submitter	literature only	Counsyl	Jul 10, 2014	- -

Hereditary cancer-predisposing syndrome Benign:4

Benign, criteria provided, single submitter	clinical testing	Vantari Genetics	Jan 06, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 05, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 19, 2014	This alteration is classified as 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. -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Dec 17, 2020	- -

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 19, 2021	This variant is associated with the following publications: (PMID: 10717622, 24504028, 15026808, 21952622, 21520273, 24323938, 19200354, 15172753, 20104584, 19491284, 18451181, 21990134, 17924331, 15695382, 19563646, 16905680, 27616075, 29036293, 32444794) -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 14, 2017	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	BRCA2: BP1, BP4, BS3:Supporting, BS4 -

Hereditary breast ovarian cancer syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 20, 2015	Variant Summary: The c.1385A>G variant involves the alteration of a non-conserved nucleotide and 2/5 in silico tools predict a benign outcome. The variant was observed in the large and broad cohorts of the ExAC project at an allele frequency of 0.023%, primarily observed in the European (Non-Finnish) cohort at a frequency of 0.041%. These frequencies do not exceed the maximal expected allele frequency for a pathogenic variant in BRCA2 (0.075%). The variant was reported in the literature and databases in individuals who also have pathogenic BRCA1 (n=1) and BRCA2 (n=3) mutations (UMD, BIC, Simard_2007) suggesting a benign nature of the variant. Additionally, the variant was found to not segregate with disease in families tested (3 affected family members did not carry the variant; Gomez Garcia_2009). Functional studies showed the variant performed similarly to wild-type BRCA2 in assays of cellular survival and viability, homologous recombination repair, and genome instability (Wu_2005). Multiple reputable databases and clinical labs all classify the variant as benign/likely benign (Emory Genteics, UMD, ARUP, Ambry Genetics, SCRP, GeneDx, Counsyl) along with publications using multifactorial probability based models (Lindor_2012, Gomez Garcia_2009). All data, including co-segregation, functional assays, co-occurrence and the occurrence of this variant in the control population all support the classification of benign, therefore this variant has been classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	14
DANN	Uncertain	0.99
Eigen	Benign	0.0072
Eigen_PC	Benign	-0.15
FATHMM_MKL	Benign	0.31	N
M_CAP	Benign	0.074	D
MetaRNN	Benign	0.12	T;T
MetaSVM	Benign	-0.98	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.0	N;N
REVEL	Benign	0.13
Sift	Benign	0.067	T;T
Sift4G	Benign	0.064	T;T
Vest4		0.23
MVP		0.90
MPC		0.022
ClinPred		0.064	T
GERP RS		5.3
gMVP		0.26

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: rs56403624; hg19: chr13-32907000; COSMIC: COSV66464441;