rs80359152

Variant names:

• chr13-32379800-G-A
• rs80359152
• NM_000059.4:c.9004G>A

Your query was ambiguous. Multiple possible variants found:

• chr13-32379800-G-A
• chr13-32379800-G-C

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1_Moderate PS3 PM2 PP5_Very_Strong

The NM_001406720.1(BRCA2):​c.8954-1G>A variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,084 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV004846104: Functional studies have reported that this variant impacts BRCA1 function in homology-mediated repair assays and the rescue of Brca2-deficient mouse embryonic stem cells (PMID:22678057, 22771033, 23108138, 29394989, 29884841, 29988080, 35736817)." and additional evidence is available in ClinVar. The gene BRCA2 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: BRCA2 NM_001406720.1 splice_acceptor, intron
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:23 U:1
• Conservation: PhyloP100: 8.92
• Publications: 53 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

Specifications for BRCA2 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.0110719185 fraction of the gene. Cryptic splice site detected, with MaxEntScore 4, offset of 3, new splice context is: atattctctgttaacaaaAGgaa. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV004846104: Functional studies have reported that this variant impacts BRCA1 function in homology-mediated repair assays and the rescue of Brca2-deficient mouse embryonic stem cells (PMID: 22678057, 22771033, 23108138, 29394989, 29884841, 29988080, 35736817).; SCV000600836: Experimental studies indicate that this variant has deleterious effects on BRCA2 protein function (PMIDs: 35736817 (2022), 29988080 (2018), 29394989 (2018), 22678057 (2012)).; SCV000883481: Functional evaluation of BRCA2 variants mapping to the PALB2-binding and C-terminal DNA-binding domains using a mouse ES cell-based assay. Hum Mol Genet. 2012 Sep 15;21(18):3993-4006. A classification model for BRCA2 DNA binding domain missense variants based on homology-directed repair activity. Cancer Res. 2013 Jan 1;73(1):265-75. BRCA2 localization to the midbody by filamin A regulates cep55 signaling and completion of cytokinesis. Dev Cell. 2012 Jul 17;23(1):137-52.; SCV000185521: This alteration has been predicted to be deleterious by multiple functional analyses (Biswas, 2012; Mondal, 2012; Guidugli, 2013; Guidugli, 2018; Mesman, 2019).; SCV000684014: Functional studies have reported that this variant impacts BRCA2 function in homology-mediated repair assays and the rescue of Brca2-deficient mouse embryonic stem cells (PMID: 22678057, 22771033, 23108138, 29394989, 29884841, 29988080, 35736817).; SCV000073698: Experimental studies have shown that this missense change affects BRCA2 function (PMID: 22678057, 22771033, 23108138).; SCV000605787: In vitro functional studies provide some evidence that the p.Glu3002Lys may impact protein function (Biswas 2012, Guidugli 2013).; SCV000695199: An extensive array of functional studies have shown E3002K to significantly interfere with homology-directed DNA repair (HDR) activity (Guidugli_2012, Mondal_2012) and ability to rescue BRCA2 -/- cells (Biswas_2012); additionally, E3002K disrupts interaction with Filamin A, localization of BRCA2 to the central spindle/midbody, and the integrity of cytokinesis (Mondal_2012).; SCV001478306: The variant has a probability of pathogenicity of 1.0 (PS3_strong).; SCV005045710: "The negative functional impact of the variant has been confirmed by the HDR assay (PMID: 23108138) and mouse ES-cell based assay (PMID: 22678057)."; SCV000592246: "However, functional studies have shown that compared to the wild-type protein, the variant affects the integrity of cytokinesis during the cell cycle, and that the DNA repair capacity of the mutant allele is compromised (Biswas_2012, Mondal_2012)."
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 13-32379800-G-A is Pathogenic according to our data. Variant chr13-32379800-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 38201.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001406720.1. 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.9004G>A	p.Glu3002Lys	missense	Exon 23 of 27	NP_000050.3	A0A7P0T9D7
	BRCA2	NM_001432077.1		c.9004G>A	p.Glu3002Lys	missense	Exon 23 of 27	NP_001419006.1	A0A7P0T9D7
	BRCA2	NM_001406719.1		c.8908G>A	p.Glu2970Lys	missense	Exon 22 of 26	NP_001393648.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA2	ENST00000380152.8	TSL:5 MANE Select	c.9004G>A	p.Glu3002Lys	missense	Exon 23 of 27	ENSP00000369497.3	P51587
	BRCA2	ENST00000544455.6	TSL:1	c.9004G>A	p.Glu3002Lys	missense	Exon 23 of 27	ENSP00000439902.1	P51587
	BRCA2	ENST00000530893.7	TSL:1	c.8635G>A	p.Glu2879Lys	missense	Exon 23 of 27	ENSP00000499438.2	A0A590UJI7

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460084 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726466

African (AFR) AF: 0.00 AC: 0 AN: 33430

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

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39648

South Asian (SAS) AF: 0.00 AC: 0 AN: 86226

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1110440

Other (OTH) AF: 0.00 AC: 0 AN: 60326

GnomAD4 genome Cov.: 33

Alfa AF: 0.00000989 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
6	-	-	Hereditary breast ovarian cancer syndrome (6)
4	1	-	Breast-ovarian cancer, familial, susceptibility to, 2 (5)
5	-	-	not provided (5)
3	-	-	Hereditary cancer-predisposing syndrome (3)
2	-	-	Breast and/or ovarian cancer (2)
2	-	-	Familial cancer of breast (2)
1	-	-	Malignant tumor of breast (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	32
DANN	Pathogenic	1.0
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Uncertain	0.48	D
PhyloP100		8.9
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.1	N
REVEL	Pathogenic	0.72
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.82
MutPred		0.82		Gain of MoRF binding (P = 0.0015)
MVP		0.96
MPC		0.17
ClinPred		0.98	D
GERP RS		5.7
gMVP		0.86
Mutation Taster		=9/91	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: rs80359152; hg19: chr13-32953937; COSMIC: COSV66460189;