rs80359024

Variant names:

• chr13-32362681-A-G
• rs80359024
• NM_000059.4:c.7964A>G

Your query was ambiguous. Multiple possible variants found:

• chr13-32362681-A-G
• chr13-32362681-A-T

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM1 PM2 PP3_Moderate PP5_Very_Strong

The NM_000059.4(BRCA2):​c.7964A>G​(p.Gln2655Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,846 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q2655H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:17 U:2
• Conservation: PhyloP100: 9.22
• Publications: 10 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: Pathogenic. The variant received 14 ACMG points.

• PM1: In a hotspot region, there are 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 5 benign, 32 uncertain in NM_000059.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.908
• PP5: Variant 13-32362681-A-G is Pathogenic according to our data. Variant chr13-32362681-A-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 52450.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.7964A>G	p.Gln2655Arg	missense_variant	Exon 17 of 27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.7964A>G	p.Gln2655Arg	missense_variant	Exon 17 of 27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.7595A>G	p.Gln2532Arg	missense_variant	Exon 17 of 27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.*22A>G		non_coding_transcript_exon_variant	Exon 16 of 26	2		ENSP00000506251.1
BRCA2	ENST00000614259.2	n.*22A>G		3_prime_UTR_variant	Exon 16 of 26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461846 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727222

African (AFR) AF: 0.00 AC: 0 AN: 33480

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: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111998

Other (OTH) AF: 0.0000166 AC: 1 AN: 60390

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:17 Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:6

May 10, 2019

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 17, 2021

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been reported with another pathogenic BRCA2 variant in trans (on a different chromosome) in an individual affected with Fanconi Anemia (PMIDs: 11430722 (2001) and 20608899 (2010)). In addition, this variant was reported to have a damaging effect on homology-directed repair in a peer-reviewed experimental study (PMID: 29394989 (2018)). This variant has not been reported in large, multi-ethnic general populations. Variant is predicted to have a damaging effect on the protein and is located in a potentially critical domain of the protein. Based on the available information, this variant is classified as pathogenic. -

Feb 26, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BRCA2 c.7964A>G; p.Gln2655Arg variant (rs80359024) is reported in the literature in an individual affected with Fanconi anemia confirmed to carry another pathogenic BRCA2 variant in trans (Bodd 2010). The p.Gln2655Arg variant is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Computational analyses are uncertain whether this variant is neutral or deleterious (BayesDel: 0.248; REVEL: 0.784). However, functional analysis of the variant protein suggests significantly reduced homology-directed repair activity similar to other pathogenic variants (Guidigli 2018). Based on available information, the p.Gln2655Arg variant is considered to be likely pathogenic. References: Bodd TL et al. Fanconi anaemia, BRCA2 and familial considerations - follow up on a previous case report. Acta Paediatr. 2010 Nov;99(11):1741-3. PMID: 20608899. Guidugli L et al. Assessment of the Clinical Relevance of BRCA2 Missense Variants by Functional and Computational Approaches. Am J Hum Genet. 2018 Feb 1;102(2):233-248. PMID: 29394989. -

Sep 25, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed in individuals undergoing multi-gene panel testing based on a personal and/or family history of cancer, as well as in individuals with breast cancer in a case-control study (PMID: 31853058, 33471991); Published functional studies demonstrate decreased homology directed repair activity (PMID: 29394989, 29884841, 35665744); In silico analysis indicates that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as c.8192A>G; This variant is associated with the following publications: (PMID: 19043619, 26064523, 11430722, 29394989, 29884841, 35665744, 31131967, 29158857, 31853058, 32377563, 33471991, 20608899, 12228710, 36721989) -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 15, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP4, PM2, PS2, PS3_moderate -

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

Dec 23, 2003

Breast Cancer Information Core (BIC) (BRCA2)

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

- -

May 28, 2019

Mendelics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 10, 2024

All of Us Research Program, National Institutes of Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces glutamine with arginine at codon 2655 of the BRCA2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study reported that this variant impacts BRCA2 function in a homology-mediated repair assay (PMID: 29394989). This variant has been detected in two individuals affected with breast cancer and absent in 53461 unaffected individuals in a breast cancer case-control meta-analysis (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_000247). This variant also has been found in trans with a pathogenic truncation variant in BRCA2 in an individual diagnosed with Fanconi anemia (PMID: 20608899). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Aug 31, 2020

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 06, 2017

Counsyl

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

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. -

Familial cancer of breast Pathogenic:3

Jun 30, 2023

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 19, 2025

Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The following ACMG criteria has been used: PM2_SUP; PS3; PP3; PM3 -

Aug 22, 2024

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Criteria applied: PS3,PM3,PM2_SUP -

Hereditary cancer-predisposing syndrome Pathogenic:2

Mar 29, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces glutamine with arginine at codon 2655 of the BRCA2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study reported that this variant impacts BRCA2 function in a homology-mediated repair assay (PMID: 29394989). This variant has been detected in two individuals affected with breast cancer and absent in 53461 unaffected individuals in a breast cancer case-control meta-analysis (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_000247). This variant also has been found in trans with a pathogenic truncation variant in BRCA2 in an individual diagnosed with Fanconi anemia (PMID: 20608899). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Mar 19, 2025

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Q2655R variant (also known as c.7964A>G), located in coding exon 16 of the BRCA2 gene, results from an A to G substitution at nucleotide position 7964. The glutamine at codon 2655 is replaced by arginine, an amino acid with highly similar properties. This alteration was detected in trans with a BRCA2 pathogenic nonsense mutation in an archived medulloblastoma sample from a deceased individual with Fanconi Anemia (Ruud E et al. Acta Paediatr. 2001 May;90:580-3; Bodd TL et al. Acta Paediatr. 2010 Nov;99:1741-3). This alteration has an intermediate impact in a homology directed DNA repair (HDR) assay (Personal communication). Two saturation genome editing-based studies, including a haploid cell-survival assay and a humanized mouse embryonic stem cell line assay of drug response and survival, demonstrate that this nucleotide substitution is functional; however these assays may not be properly calibrated to measure the function of hypomorphic variants (Huang H et al. Nature. 2025 Feb;638(8050):528-537; Sahu S et al. Nature. 2025 Feb;638(8050):538-545). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. However, because this variant is identified in one or more patients with Fanconi Anemia it may be hypomorphic and thus, carriers of this variant and their families may present with reduced risks, and not with the typical clinical characteristics of a high-risk pathogenic BRCA2 alteration. As risk estimates are unknown at this time, clinical correlation is advised. -

Hereditary breast ovarian cancer syndrome Pathogenic:2

Jan 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 2655 of the BRCA2 protein (p.Gln2655Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Fanconi anemia (PMID: 20608899). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This missense change has been observed to co-occur in individuals with a different variant in BRCA2 that has been determined to be pathogenic (internal data), but the significance of this finding is unclear. ClinVar contains an entry for this variant (Variation ID: 52450). An algorithm developed specifically for the BRCA2 gene suggests that this missense change is likely to be deleterious (internal data). Experimental studies have shown that this missense change affects BRCA2 function (PMID: 29394989, 29884841). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Oct 04, 2023

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.7964A>G variant in the BRCA2 gene is located in exon 17, and replaces glutamine with arginine at codon 2655 (p.Gln2655Arg) in the BRCA2 protein. This variant has been reported in individuals affected with breast cancer (PMID: 33471991) and in an individual affected with Fanconi Anemia (PMID: 20608899). Experimental studies have shown that this variant has a deleterious effect in a homology directed DNA repair (HDR) assay (PMID: 29394989, 29884841). ClinVar contains an entry for this variant (ID: 52450). This variant is absent in the general population according to gnomAD. In silico prediction algorithms suggest that this variant may have deleterious impact on protein structure and function. Therefore, the c.7964A>G (p.Gln2655Arg) variant in the BRCA2 gene is classified as likely pathogenic. -

Fanconi anemia Pathogenic:1

Dec 06, 2024

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: BRCA2 c.7964A>G (p.Gln2655Arg) results in a conservative amino acid change located in the BRCA2, helical domain (Integrated: IPR015252) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251260 control chromosomes. c.7964A>G has been reported in the literature as a biallelic compound heterozygous genotype in at-least one individual affected with Fanconi Anemia (example, Bodd_2010 cited in Miele_2015). At least two publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in loss of homology directed repair (HDR) of normal activity (example, Guidugli_2018, Hart_2019). HDR assays qualify as a recognized gold standard on the basis of updated guidance provided by the ClinGen Sequence Variant Interpretation (SVI) working group. This working group has recommended strong functional evidence (ACMG PS3) as sufficient weightage for categorization as likely pathogenic (Tavtigian_2018). The following publications have been ascertained in the context of this evaluation (PMID: 20608899, 29394989, 29884841, 19043619, 34687993, 26064523, 36721989). ClinVar contains an entry for this variant (Variation ID: 52450). Based on the evidence outlined above, the variant was classified as likely pathogenic for autosomal recessive Fanconi Anemia and autosomal dominant Breast Cancer susceptibility. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	26
DANN	Uncertain	1.0
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Pathogenic	0.33	D
MetaRNN	Pathogenic	0.91	D;D
MetaSVM	Pathogenic	0.82	D
PhyloP100		9.2
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-1.1	N;N
REVEL	Pathogenic	0.78
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Vest4		0.84
MutPred		0.82		Gain of MoRF binding (P = 0.0106);Gain of MoRF binding (P = 0.0106);
MVP		0.97
MPC		0.17
ClinPred		0.98	D
GERP RS		5.7
gMVP		0.80
Mutation Taster		=4/96	disease causing (ClinVar)

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: rs80359024; hg19: chr13-32936818;