rs80359800

Variant names:

• chr13-32363194-T-A
• rs80359800
• NM_000059.4:c.7992T>A

Your query was ambiguous. Multiple possible variants found:

• chr13-32363194-T-A
• chr13-32363194-T-C
• chr13-32363194-T-G

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP6_Very_Strong BP7

The NM_000059.4(BRCA2):​c.7992T>A​(p.Ile2664Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000366 in 1,613,670 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★★). Synonymous variant affecting the same amino acid position (i.e. I2664I) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000039 (0 hom.)
• Consequence: BRCA2 NM_000059.4 synonymous
• Clinical Significance: Likely benign reviewed by expert panel P:1 U:4 B:12
• Conservation: PhyloP100: 0.633
• Publications: 22 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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.34).
• BP6: Variant 13-32363194-T-A is Benign according to our data. Variant chr13-32363194-T-A is described in ClinVar as Likely_benign. ClinVar VariationId is 52463.Status of the report is reviewed_by_expert_panel, 3 stars.
• BP7: Synonymous conserved (PhyloP=0.633 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.7992T>A	p.Ile2664Ile	synonymous_variant	Exon 18 of 27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.7992T>A	p.Ile2664Ile	synonymous_variant	Exon 18 of 27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.7623T>A	p.Ile2541Ile	synonymous_variant	Exon 18 of 27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.*50T>A		non_coding_transcript_exon_variant	Exon 17 of 26	2		ENSP00000506251.1
BRCA2	ENST00000614259.2	n.*50T>A		3_prime_UTR_variant	Exon 17 of 26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152132 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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

GnomAD2 exomes AF: 0.0000319 AC: 8 AN: 250460 AF XY: 0.0000221

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: 0.0000707

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000390 AC: 57 AN: 1461420 Hom.: 0 Cov.: 31 AF XY: 0.0000413 AC XY: 30 AN XY: 727022

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.00 AC: 0 AN: 86228

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53142

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000486 AC: 54 AN: 1111892

Other (OTH) AF: 0.0000331 AC: 2 AN: 60384

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152250 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74452

African (AFR) AF: 0.00 AC: 0 AN: 41520

American (AMR) AF: 0.0000654 AC: 1 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.0000589 Hom.: 0

Bravo AF: 0.0000264

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Pathogenic:1 Uncertain:4 Benign:12

Revision: reviewed by expert panel

Submissions by phenotype

not provided Uncertain:2 Benign:3

Nov 09, 2017

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is denoted BRCA2 c.7992T>A at the DNA level. Using alternate nomenclature, this variant would be defined as BRCA2 8220T>A. Although the variant is silent at the coding level, preserving an Isoleucine at codon 2664, it has been demonstrated to cause abnormal splicing. However, the splicing error has been characterized as having a partial, or leaky, effect, with some full length transcript also being produced (Th?ry 2011, Houdayer 2012). BRCA2 c.7992T>A has been reported in a patient with bilateral breast cancer and a family history of early onset breast cancer (Th?ry 2011). BRCA2 c.7992T>A was not observed at a significant allele frequency in large population cohorts (Lek 2016). The nucleotide which is altered, a thymine (T) at base 7992, is conserved among mammals. Based on currently available information, it is unclear whether BRCA2 c.7992T>A is pathogenic or benign. We consider it to be a variant of uncertain significance. -

Mar 07, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BP6, BP7, PS3_supporting -

-

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

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

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

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 17, 2021

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Jun 29, 2017

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

Significance: Likely benign

Review Status: reviewed by expert panel

Collection Method: curation

Synonymous substitution variant, with low bioinformatic likelihood to result in a splicing aberration (Splicing prior probability 0.02; http://priors.hci.utah.edu/PRIORS/). -

Mar 02, 2020

BRCAlab, Lund University

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:2

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 24, 2025

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: BRCA2 c.7992T>A alters a conserved nucleotide resulting in a synonymous change. Consensus agreement among computation tools predict no significant impact on normal splicing. Splicing functional assays demonstrated the variant increases skipping of exon 18 (Thery_2011, Houdayer_2012, Fraile-Bethencourt_2017, Wangensteen_2019), however it is complex to interpret the role of variants with partial splicing anomalies in HBOC under the clinical perspective. The variant allele was found at a frequency of 3.2e-05 in 250460 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.7992T>A has been reported in the literature in an individual affected with breast cancer (Thery_2011). These data do not allow any conclusion about variant significance. At least one publication reports experimental evidence evaluating an impact HDR function, finding no deleterious effect (Mesman_2020). The following publications have been ascertained in the context of this evaluation (PMID: 22505045, 21673748, 23893897, 22962691, 26332594, 26913838, 28339459, 28758972, 31191615, 28794409, 31143303, 32398771). ClinVar contains an entry for this variant (Variation ID: 52463). Based on the evidence outlined above, the variant was classified as likely benign. -

Hereditary cancer-predisposing syndrome Benign:2

Dec 04, 2015

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 15, 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. -

Hereditary breast ovarian cancer syndrome;C2675520:Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:1

Sep 01, 2019

King Laboratory, University of Washington

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Breast and/or ovarian cancer Uncertain:1

Aug 07, 2015

Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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.Ile2664Ile has been identified in UMD (6X) and the BIC (1X) databases. It is listed in dbSNP database coming from a “clinical source” (ID#: rs80359800) with a “global minor allele frequency of less than 0.001 (1000 genomes). This variant is not expected to have clinical significance because it does not alter an amino acid residue, however it has been suggested to induce incomplete skipping of exon 18 of BRCA2 detected by minigene and in vivo assays (Thery 2011); yet in–silico or computational prediction software (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predicts no change in the splice site prediction score. In summary, the clinical significance of this variant cannot be determined with certainty at this time. Therefore this variant is a variant of unknown significance (VUS). -

BRCA2-related disorder Benign:1

Dec 27, 2020

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Hereditary breast ovarian cancer syndrome Benign:1

Feb 01, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.34
CADD	Benign	6.5
DANN	Benign	0.68
PhyloP100		0.63
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		3.0
SpliceAI score (max)		0.020		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: rs80359800; hg19: chr13-32937331;