rs80359064

Variant names:

• chr13-32363379-A-G
• rs80359064
• NM_000059.4:c.8177A>G

Your query was ambiguous. Multiple possible variants found:

• chr13-32363379-A-G
• chr13-32363379-A-T
• chr13-32363379-A-C

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PS3 PM1 PM2 PM5 PP3_Moderate PP5_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 (★★). ClinVar reports functional evidence for this variant: "SCV000073455: Experimental studies have shown that this missense change affects BRCA2 function (PMID:23108138, 29394989, 33293522, 35736817).; SCV004039112: "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)."; SCV000185557: 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).; SCV002053651: 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).; SCV006324819: Reported by calibrated studies to affect protein function similar to pathogenic control variants (PMID:29394989, 29884841, 33293522, 33609447) (PS3).; SCV000210466: 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); SCV004010227: PS3:Supporting; SCV004220591: 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)).; SCV004565188: 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. 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.; SCV004845618: 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).". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y2726F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13 U:3
• Conservation: PhyloP100: 8.95
• Publications: 27 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):

• BRCA2-related cancer predisposition

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• breast-ovarian cancer, familial, susceptibility to, 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• Fanconi anemia complementation group D1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
• 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 20 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000073455: Experimental studies have shown that this missense change affects BRCA2 function (PMID: 23108138, 29394989, 33293522, 35736817).; SCV004039112: "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)."; SCV000185557: 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).; SCV002053651: 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).; SCV006324819: Reported by calibrated studies to affect protein function similar to pathogenic control variants (PMID: 29394989, 29884841, 33293522, 33609447) (PS3).; SCV000210466: 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); SCV004010227: PS3:Supporting; SCV004220591: 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)).; SCV004565188: 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. 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.; SCV004845618: 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).
• PM1: In a hotspot region, there are 19 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 15 benign, 25 uncertain in NM_000059.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr13-32363378-T-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1505734.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 52520.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA2	NM_000059.4	MANE Select	c.8177A>G	p.Tyr2726Cys	missense	Exon 18 of 27	NP_000050.3	A0A7P0T9D7
	BRCA2	NM_001432077.1		c.8177A>G	p.Tyr2726Cys	missense	Exon 18 of 27	NP_001419006.1	A0A7P0T9D7
	BRCA2	NM_001406720.1		c.8177A>G	p.Tyr2726Cys	missense	Exon 18 of 27	NP_001393649.1	A0A8V8TPZ2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA2	ENST00000380152.8	TSL:5 MANE Select	c.8177A>G	p.Tyr2726Cys	missense	Exon 18 of 27	ENSP00000369497.3	P51587
	BRCA2	ENST00000544455.6	TSL:1	c.8177A>G	p.Tyr2726Cys	missense	Exon 18 of 27	ENSP00000439902.1	P51587
	BRCA2	ENST00000530893.7	TSL:1	c.7808A>G	p.Tyr2603Cys	missense	Exon 18 of 27	ENSP00000499438.2	A0A590UJI7

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152226 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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461868 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727232

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

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86256

European-Finnish (FIN) AF: 0.0000374 AC: 2 AN: 53420

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

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112002

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152226 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74382

African (AFR) AF: 0.00 AC: 0 AN: 41456

American (AMR) AF: 0.00 AC: 0 AN: 15288

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5204

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

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: 0.0000147 AC: 1 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	3	-	Breast-ovarian cancer, familial, susceptibility to, 2 (5)
4	-	-	not provided (4)
3	-	-	Hereditary cancer-predisposing syndrome (3)
2	-	-	Hereditary breast ovarian cancer syndrome (2)
1	-	-	BRCA2-related cancer predisposition (1)
1	-	-	Familial cancer of breast (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	26
DANN	Uncertain	1.0
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Pathogenic	1.1	D
PhyloP100		8.9
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-2.7	D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.89
MVP		0.97
MPC		0.18
ClinPred		1.0	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.90
Mutation Taster		=1/99	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: rs80359064; hg19: chr13-32937516; COSMIC: COSV66448413; COSMIC: COSV66448413;