chr13-32338037-A-G

Variant names:

• chr13-32338037-A-G
• rs28897722
• NM_000059.4:c.3682A>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4 BP6_Very_Strong

The NM_000059.4(BRCA2):​c.3682A>G​(p.Asn1228Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000515 in 1,611,922 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 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. N1228K) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000053 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Benign reviewed by expert panel U:2 B:18
• Conservation: PhyloP100: 1.46
• Publications: 16 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: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.38751778).
• BP6: Variant 13-32338037-A-G is Benign according to our data. Variant chr13-32338037-A-G is described in ClinVar as Benign. ClinVar VariationId is 37852.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.3682A>G	p.Asn1228Asp	missense_variant	Exon 11 of 27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.3682A>G	p.Asn1228Asp	missense_variant	Exon 11 of 27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.3313A>G	p.Asn1105Asp	missense_variant	Exon 11 of 27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.3682A>G		non_coding_transcript_exon_variant	Exon 10 of 26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152196 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: 0.0000735

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000401 AC: 10 AN: 249496 AF XY: 0.0000445

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: 0.0000796

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000534 AC: 78 AN: 1459726 Hom.: 0 Cov.: 35 AF XY: 0.0000468 AC XY: 34 AN XY: 725924

African (AFR) AF: 0.00 AC: 0 AN: 33368

American (AMR) AF: 0.00 AC: 0 AN: 44432

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26044

East Asian (EAS) AF: 0.00 AC: 0 AN: 39672

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 85912

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53336

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.0000657 AC: 73 AN: 1110946

Other (OTH) AF: 0.0000664 AC: 4 AN: 60264

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152196 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74366

African (AFR) AF: 0.00 AC: 0 AN: 41462

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.000108 Hom.: 0

Bravo AF: 0.0000604

ExAC AF: 0.0000494 AC: 6

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Uncertain:2 Benign:18

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:1 Benign:8

Sep 21, 2015

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

May 29, 2002

Breast Cancer Information Core (BIC) (BRCA2)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jul 28, 2017

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Oct 31, 2014

Counsyl

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: literature only

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The BRCA2 p.Asn1228Asp variant was identified in a minimum of 1 of 146 proband chromosomes (frequency: 0.007) from Italian individuals or families with breast/ovarian cancers (Giannini 2006). Computational methods assessing the pathogenicity of unclassified missense variants includes a posterior probability model/likelihood ratio model found the variant not to be deleterious (Lindor 2012, Easton 2007, Rajasekaran 2008). The variant was also identified in dbSBP (ID: rs28897722) “With other allele”, ClinVar (classified as benign, reviewed by an expert panel (last assessed 2015); submitters: benign by ENIGMA, Invitae, Ambry Genetics, SCRP (Sharing Clinical Reports Project, derived from Myriad reports); likely benign by GeneDx, Counsyl; uncertain significance by BIC and Div of Genomic Diagnostics, Children's Hospital of Philadelphia), Clinvitae (4x), LOVD 3.0 (4x), UMD-LSDB (7x with classification 1-Neutral), BIC Database (7x, unknown clinical importance, classification pending), and ARUP Laboratories (classified 1-not pathogenic or of no clinical significance). The variant was not identified in Genesight-COGR, Cosmic, MutDB, Zhejiang Colon Cancer Database. The variant was identified in control databases in 11 of 275416 chromosomes at a frequency of 0.00004 increasing the likelihood that this may be a low frequency benign variant in certain populations of origin (Genome Aggregation Consortium Feb 27, 2017). The p.Asn1228 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.

Aug 10, 2015

Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: curation

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 = 0.00000548

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

May 28, 2019

Mendelics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

May 01, 2012

Sharing Clinical Reports Project (SCRP)

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

not specified Benign:3

Oct 27, 2020

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: BRCA2 c.3682A>G (p.Asn1228Asp) results in a conservative amino acid change located in the BRCA2 repeat of 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 4e-05 in 249496 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in BRCA2 causing Hereditary Breast And Ovarian Cancer Syndrome (4e-05 vs 0.00075), allowing no conclusion about variant significance. c.3682A>G has been reported in the literature in cohorts of individuals with breast cancer (example, Capalbo_2006, DeBrakeleer_2015, Giannini_2006, Romano_2007, Seymour_2008, Maxwell_2016, Ikeda_2016). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Multifactorial probability models have reported a neutral outcome for this variant (Lindor_2012). At-least two co-occurrences with another pathogenic variant have been reported in the BIC database (BRCA2 c.6468_6469delTC, p.Ser2156_Gln2157SerIlefs), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function by a high throughput functional screen (Ikegami_2020). These results showed no damaging effect of this variant as measured by tolerance to treatment with PARP inhibitors. Eight clinical diagnostic laboratories and one expert panel (ENIGMA, classification as benign) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (benign, n=3, likely benign, n=4, VUS, n=1). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the absence of conclusive evidence supporting an actionable outcome as outlined above and to reflect the majority consensus classification in the field, the variant was classified as benign.

Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

not provided Benign:3

Mar 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BRCA2: BP4

Jan 24, 2018

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jun 10, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 18724707, 27153395, 17924331, 24323938, 26010302, 16847550, 16760289, 21990134, 32444794)

Hereditary cancer-predisposing syndrome Benign:3

Nov 19, 2014

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Mar 14, 2021

Sema4, Sema4

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

Mar 10, 2015

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hereditary breast ovarian cancer syndrome Uncertain:1 Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 20, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0	.;.
Eigen	Benign	-0.0074
Eigen_PC	Benign	-0.10
FATHMM_MKL	Benign	0.46	N
LIST_S2	Benign	0.0	.;.
M_CAP	Benign	0.061	D
MetaRNN	Benign	0.39	T;T
MetaSVM	Benign	-0.61	T
MutationAssessor	Benign	0.0	.;.
PhyloP100		1.5
PrimateAI	Benign	0.31	T
PROVEAN	Uncertain	-3.6	D;D
REVEL	Uncertain	0.44
Sift	Uncertain	0.026	D;D
Sift4G	Benign	0.071	T;T
Vest4		0.28
ClinPred		0.41	T
GERP RS		3.4
gMVP		0.13
Mutation Taster		=77/23	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: rs28897722; hg19: chr13-32912174;