13-32363379-A-G

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong

The NM_000059.4(BRCA2):c.8177A>G(p.Tyr2726Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,614,094 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 (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

BRCA2
NM_000059.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12U:3

Conservation

PhyloP100: 8.95

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.912

PP5

Variant 13-32363379-A-G is Pathogenic according to our data. Variant chr13-32363379-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 52520.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 link	c.8177A>G	p.Tyr2726Cys	missense_variant	Exon 18 of 27	ENST00000380152.8	NP_000050.3	P51587

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
BRCA2	ENST00000380152.8 link	c.8177A>G	p.Tyr2726Cys	missense_variant	Exon 18 of 27	5	NM_000059.4	ENSP00000369497.3	P51587
BRCA2	ENST00000530893.7 link	c.7808A>G	p.Tyr2603Cys	missense_variant	Exon 18 of 27	1		ENSP00000499438.2	A0A590UJI7
BRCA2	ENST00000614259.2 link	n.*235A>G		non_coding_transcript_exon_variant	Exon 17 of 26	2		ENSP00000506251.1	A0A7P0TAP7
BRCA2	ENST00000614259 link	n.*235A>G		3_prime_UTR_variant	Exon 17 of 25	2		ENSP00000506251.1	A0A7P0TAP7

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152226

Hom.:

Cov.:

show subpopulations

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461868

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727232

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0000374

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152226

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74382

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2

Pathogenic:2Uncertain:3

Mar 02, 2020

BRCAlab, Lund University

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 25, 2015

Department of Medical Genetics, Oslo University Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 30, 2012

Sharing Clinical Reports Project (SCRP)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 23, 2003

Breast Cancer Information Core (BIC) (BRCA2)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 01, 2016

Department of Medical Genetics, University Hospital of North Norway

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided

Pathogenic:4

Mar 03, 2025

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed in individuals with a personal or family history of breast, ovarian, pancreatic, or other cancers (PMID: 25452441, 27495310, 29338080, 38843470); Published functional studies demonstrate a damaging effect: decreased homology-directed DNA break repair activity and inability to rescue cell lethality in a null cell line (PMID: 23108138, 29884841, 33293522, 39779857, 39779848); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 8405A>G; This variant is associated with the following publications: (PMID: 24323938, 28888541, 19043619, 25452441, 23108138, 27495310, 29394989, 29339979, 29338080, 32042831, 31853058, 29884841, 32875559, 33293522, 35665744, 35736817, 33609447, 36922933, 36467798, 33471991, 36551643, 39779857, 39779848, 38843470, 12228710) -

Apr 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BRCA2: PM2, PS4:Moderate, PP1, PS3:Supporting -

Jul 16, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BRCA2 c.8177A>G (p.Tyr2726Cys) variant has been reported in the published literature in individuals/families affected with breast and/or ovarian cancer (PMIDs: 25452441 (2015), 27495310 (2016), 28888541 (2017), 29339979 (2018), 36551643 (2022), 33471991 (2021) and LOVD (http://databases.lovd.nl/shared/genes/BRCA2)), prostate cancer (PMID: 32875559 (2020)), and multiple myeloma-plasma cell leukemia (PMID: 36467798 (2022)). Functional studies have demonstrated this variant to be non-functional due to deficient homology-directed repair (HDR) (PMIDs: 23108138 (2013), 29394989 (2018), 33293522 (2020), 33609447 (2021), 35736817 (2022)). The frequency of this variant in the general population, 0.0000066 (1/152226 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as likely pathogenic. -

Jan 04, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BRCA2 c.8177A>G; p.Tyr2726Cys variant (rs80359064) is reported in the literature in individuals with BRCA2-associated cancers (Couch 2015, Heramb 2018, Lilyquist 2017, Wokolorczyk 2020), and reported to have impaired homology-directed repair activity (Guidugli 2018, Hu 2022). This variant is also reported by multiple laboratories in ClinVar (Variation ID: 52520). It is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.928). Based on available information, this variant is considered to be pathogenic. References: Couch FJ et al. Inherited mutations in 17 breast cancer susceptibility genes among a large triple-negative breast cancer cohort unselected for family history of breast cancer. J Clin Oncol. 2015 Feb 1;33(4):304-11. PMID: 25452441. 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. Heramb C et al. BRCA1 and BRCA2 mutation spectrum - an update on mutation distribution in a large cancer genetics clinic in Norway. Hered Cancer Clin Pract. 2018 Jan 10;16:3. PMID: 29339979. Hu C et al. Classification of BRCA2 Variants of Uncertain Significance (VUS) Using an ACMG/AMP Model Incorporating a Homology-Directed Repair (HDR) Functional Assay. Clin Cancer Res. 2022 Sep 1;28(17):3742-3751. PMID: 35736817. Lilyquist J et al. Frequency of mutations in a large series of clinically ascertained ovarian cancer cases tested on multi-gene panels compared to reference controls. Gynecol Oncol. 2017 Nov;147(2):375-380. PMID: 28888541. Wokolorczyk D et al. Mutations in ATM, NBN and BRCA2 predispose to aggressive prostate cancer in Poland. Int J Cancer. 2020 Nov 15;147(10):2793-2800. PMID: 32875559. -

Hereditary cancer-predisposing syndrome

Pathogenic:2

Mar 12, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces tyrosine with cysteine at codon 2726 of the BRCA2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function. Functional studies have reported that this variant impact BRCA2 function in homology-mediated repair assay (PMID: 23108138, 29394989, 33609447, 35736817) and stable expression in and rescue of Brca2-deficient mouse embryonic stem cells (PMID: 33293522). This variant has been reported in individuals affected with breast cancer (PMID: 25452441, 33471991; Leiden Open Variation Database DB-ID BRCA2_000294, 36551643) and in suspected hereditary breast and ovarian cancer families (PMID: 27495310, 29339979) and an individual affected with prostate cancer (PMID: 33293522). 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. -

Jun 14, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Y2726C variant (also known as c.8177A>G), located in coding exon 17 of the BRCA2 gene, results from an A to G substitution at nucleotide position 8177. The tyrosine at codon 2726 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in multiple individuals with clinical histories suggestive of HBOC (Couch FJ et al. J. Clin. Oncol. 2015 Feb;33(4):304-11; Jarhelle E et al. Fam. Cancer. 2017 Jan;16(1):1-16; Heramb C et al. Hered Cancer Clin Pract. 2018 Jan;16:3). In one study, this variant was analyzed using protein likelihood ratio, a probabilistic likelihood ratio predictive of whether a missense variant impairs protein function, and was predicted to have a deleterious effect (Karchin R et al. Cancer Inform. 2008 Apr;6:203-16). This variant was non-functional in a homology-directed DNA repair (HDR) assay (Guidugli L et al. Cancer Res. 2013 Jan;73:265-75; Guidugli L et al. Am. J. Hum. Genet. 2018 Jan; Hart SN et al. Genet. Med., 2019 01;21:71-80). Of note, this alteration is also designated as 8405A>G in published literature. Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Yang H et al. Science 2002 Sep;297:1837-48; Ambry Internal Data). As such, this alteration is interpreted as a disease-causing mutation. -

Hereditary breast ovarian cancer syndrome

Pathogenic:2

Aug 12, 2023

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.8177A>G (p.Tyr2726Cys) results in a non-conservative amino acid change located in the BRCA2, OB1 (IPR015187) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250998 control chromosomes. c.8177A>G has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (Examples: Couch_2015, Jarhelle_2016, Nurmi_2022, Cunningham_2014) and a patient with Pancreatic adenocarcinoma (O'Reily_2018). One publication reports experimental evidence demonstrating it's inability to rescue cell lethality in a null cell line (Biswas_2020) and several report damaging impact on homology-mediated repair assay (Examples: Guidugli_2018, Richardson_2021). The HDR assay qualifies as a standardized gold-standard assay on the basis of the updated guidance provided by the ClinGen Sequence Variant Interpretation (SVI) Working Group (Brnich_2019). The following publications have been ascertained in the context of this evaluation (PMID: 20215541, 19043619, 33293522, 25452441, 24504028, 23108138, 24323938, 29394989, 27495310, 36551643, 29338080, 33609447). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classify as VUS (n=1), likely pathogenic (n=5) and pathogenic (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Aug 31, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 2726 of the BRCA2 protein (p.Tyr2726Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of hereditary breast, ovarian, prostate, and/or pancreatic cancer (PMID: 25452441, 27495310, 28888541, 29338080, 32875559, 36551643). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 52520). Invitae Evidence Modeling incorporating data from in vitro experimental studies (PMID: 33609447) indicates that this missense variant is expected to disrupt BRCA2 function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects BRCA2 function (PMID: 23108138, 29394989, 33293522, 35736817). 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. -

BRCA2-related cancer predisposition

Pathogenic:1

Apr 25, 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 tyrosine with cysteine at codon 2726 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). Functional studies have reported that this variant impact BRCA2 function in homology-mediated repair assay (PMID: 23108138, 29394989, 33609447, 35736817) and stable expression in and rescue of Brca2-deficient mouse embryonic stem cells (PMID: 33293522). This variant has been reported in at least two individuals affected with breast cancer (PMID: 25452441, 33471991; Leiden Open Variation Database DB-ID BRCA2_000294) and suspected hereditary breast and ovarian cancer families (PMID: 27495310, 29339979) and an individual affected with prostate cancer (PMID: 33293522). 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. -

Familial cancer of breast

Pathogenic:1

Mar 10, 2024

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.89

BayesDel_addAF

Pathogenic

0.54

BayesDel_noAF

Pathogenic

0.54

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

0.82

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Pathogenic

0.99

M_CAP

Pathogenic

0.38

MetaRNN

Pathogenic

0.91

D;D

MetaSVM

Pathogenic

1.1

PrimateAI

Benign

0.44

PROVEAN

Uncertain

-2.7

D;D

REVEL

Pathogenic

0.93

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Vest4

0.89

MVP

0.97

MPC

0.18

ClinPred

1.0

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

gMVP

0.90

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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