13-32394707-A-G

Variant names:

• chr13-32394707-A-G
• rs80359195
• NM_000059.4:c.9275A>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM1 PP3 BP6

The NM_000059.4(BRCA2):​c.9275A>G​(p.Tyr3092Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000657 in 1,613,290 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y3092F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000067 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:15
• Conservation: PhyloP100: 6.06
• Publications: 32 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: Uncertain_significance. The variant received 2 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 16 benign, 22 uncertain in NM_000059.4
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.838
• BP6: Variant 13-32394707-A-G is Benign according to our data. Variant chr13-32394707-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 52800.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000059.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA2	NM_000059.4	MANE Select	c.9275A>G	p.Tyr3092Cys	missense	Exon 25 of 27	NP_000050.3
	BRCA2	NM_001432077.1		c.9275A>G	p.Tyr3092Cys	missense	Exon 25 of 27	NP_001419006.1
	BRCA2	NM_001406720.1		c.9224A>G	p.Tyr3075Cys	missense	Exon 25 of 27	NP_001393649.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA2	ENST00000380152.8	TSL:5 MANE Select	c.9275A>G	p.Tyr3092Cys	missense	Exon 25 of 27	ENSP00000369497.3
	BRCA2	ENST00000544455.6	TSL:1	c.9275A>G	p.Tyr3092Cys	missense	Exon 25 of 27	ENSP00000439902.1
	BRCA2	ENST00000530893.7	TSL:1	c.8906A>G	p.Tyr2969Cys	missense	Exon 25 of 27	ENSP00000499438.2

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152040 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000758 AC: 19 AN: 250616 AF XY: 0.0000812

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000618

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000671 AC: 98 AN: 1461250 Hom.: 0 Cov.: 31 AF XY: 0.0000729 AC XY: 53 AN XY: 726902

African (AFR) AF: 0.0000598 AC: 2 AN: 33470

American (AMR) AF: 0.000157 AC: 7 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39684

South Asian (SAS) AF: 0.000128 AC: 11 AN: 86196

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53386

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5760

European-Non Finnish (NFE) AF: 0.0000621 AC: 69 AN: 1111582

Other (OTH) AF: 0.000116 AC: 7 AN: 60364

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152040 Hom.: 0 Cov.: 32 AF XY: 0.0000539 AC XY: 4 AN XY: 74262

African (AFR) AF: 0.0000242 AC: 1 AN: 41374

American (AMR) AF: 0.000131 AC: 2 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10588

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

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68006

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000477 Hom.: 0

Bravo AF: 0.0000529

ExAC AF: 0.0000659 AC: 8

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:15

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Jan 15, 2015

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.

Feb 20, 2004

Breast Cancer Information Core (BIC) (BRCA2)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Mar 18, 2016

Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: reference population

Sep 21, 2015

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jun 14, 2012

Sharing Clinical Reports Project (SCRP)

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:3

May 10, 2019

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dec 02, 2024

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.9275A>G (p.Tyr3092Cys) results in a non-conservative amino acid change located in the BRCA2, oligonucleotide/oligosaccharide-binding, domain 3 (IPR015188) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7.6e-05 in 250616 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in BRCA2 causing Hereditary Breast And Ovarian Cancer Syndrome (7.6e-05 vs 0.00075). c.9275A>G has been reported in the presumed heterozygous state in the literature in individuals suspected of or affected with Hereditary Breast And Ovarian Cancer Syndrome, without strong evidence for causality (e.g. Lee_2008, Caux-Moncoutier_2009, Juwle_2012, Peixoto_2014, Kowalik_2018, Santonocito_2020, Park_2021). Therefore, these reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. A co-occurrence with another pathogenic variant has been reported in the UMD database (BRCA2 c.6275_6276delTT, p.Leu2092ProfsX7), providing supporting evidence for a benign role. Several publications report experimental evidence evaluating an impact on protein function. These studies found that the variant has no impact on splicing and has normal HDR activity (e.g. Caux-Moncoutier_2009, Houdayer_2012, Guidugli_2012). HDR assays qualify as a recognized gold standard on the basis of updated guidance provided by the ClinGen Sequence Variant Interpretation (SVI) working group. The following publications have been ascertained in the context of this evaluation (PMID: 19471317, 21120943, 17924331, 23108138, 22505045, 22752604, 19043619, 30040829, 18284688, 21990134, 10717622, 25348012, 34063308, 24916970, 12427538, 32438681). ClinVar contains an entry for this variant (Variation ID: 52800). Based on the evidence outlined above, the variant was classified as benign.

not provided Benign:3

Mar 31, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.Tyr3092Cys variant was identified in 3 of 7064 proband chromosomes (frequency: 0.0004) from Portugese, French and American individuals or families with (hereditary) breast and ovarian cancer (Peixoto 2015, Lee 2008 , Malone 2000, Caux-Moncoutier 2011). Functional assays looking at allelic imbalance, homologous directed DNA repair (HDR) and splicing of the variant did not show any defects and the variant was classified as likely not pathogenic (Caux-Moncoutier 2009, Guidugli 2013, Houdayer 2012). In silico models (protein likelihood ratio and multifactorial probability) also classify the variant as neutral/likely benign (Karchin 2008, Lindor 2012, Easton 2007). The variant is reported in ClinVar (Conflicting interpretations of pathogenicity. Benign by Mendelics in 2019. Likely benign by Counsyl in 2015, Integrated Genetics in 2017, GeneDx in 2017, Invitae in 2019, ARUP Laboratories in 2019, Quest Diagnostics in 2019, Ambry in 2018, Color in 2016, SCRP in 2012, Foulkes Cancer Genetics LDI in 2010. Uncertain significance by BIC in 2004, Erasmus Medical Unit in 2015, PLM at Sinai Health System in 2015, Genome Diagnostics Laboratory at Utrecht Universitiy Medical Cenre in 2014, Soonchunhyang University Bucheon Hospital in 2016), LOVD 2.0 (20 entries, 16x VUS, 1x LB, 1x B), ARUP laboratories (2 - Likely not pathogenic or of little clinical significance) databases. The variant was identified in dbSNP (rs80359195) as Uncertain significance. The variant was identified by our laboratory in 1 individual with breast cancer. The variant was identified in control databases in 20 of 281996 chromosomes at a frequency of 0.00007092 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: South Asian in 5 of 30528 chromosomes (freq: 0.000164), Latino in 5 of 35332 chromosomes (freq: 0.000142), Other in 1 of 7194 chromosomes (freq: 0.000139), European (non-Finnish) in 8 of 128648 chromosomes (freq: 0.000062), East Asian in 1 of 19938 chromosomes (freq: 0.00005), but was not observed in the African, Ashkenazi Jewish, or European (Finnish) populations. UMD reports the variant to co-occur with a pathogenic BRCA2 variant, c.6275_6276delTT (p.Leu2092ProfsX7) (from Integrated Genetics ClinVar blurb, SCV000695231.1). The p.Tyr3092 residue is conserved in mammals and more distantly related organisms, and 8 out of 8 computational predictors (MUT Assesor, SIFT, Polyphen2, MT, FATHMM, DANN, MetaLR, Revel) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and 3 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. In summary, the clinical significance of this variant cannot be determined at this time, though we would lean toward a more benign role for this variant. This variant is classified as likely benign.

Apr 29, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 31131967, 32438681, 17924331, 21990134, 19043619, 22505045, 25782689, 10717622, 23108138, 19471317, 21120943, 24916970, 29394989, 18284688, 30040829, 25348012, 12427538, 29625052, 29884841, 32806537)

Hereditary cancer-predisposing syndrome Benign:2

Nov 05, 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.

Sep 16, 2016

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hereditary breast ovarian cancer syndrome Benign:2

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 19, 2022

National Health Laboratory Service, Universitas Academic Hospital and University of the Free State

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breast and/or ovarian cancer Benign:1

Apr 21, 2010

Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

BRCA2-related disorder Benign:1

Apr 15, 2019

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).

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Pathogenic	0.39
CADD	Uncertain	25
DANN	Uncertain	1.0
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Uncertain	0.76	D
PhyloP100		6.1
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-2.6	D
REVEL	Pathogenic	0.81
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.95
MVP		0.96
MPC		0.18
ClinPred		0.34	T
GERP RS		5.9
gMVP		0.71
Mutation Taster		=24/76	disease causing

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: rs80359195; hg19: chr13-32968844; COSMIC: COSV99061634;