rs1060502459

Variant names:

• chr13-32362593-T-A
• rs1060502459
• NM_000059.4:c.7876T>A

Your query was ambiguous. Multiple possible variants found:

• chr13-32362593-T-A
• chr13-32362593-T-C
• chr13-32362593-T-G

Variant summary

Our verdict is Pathogenic. The variant received 30 ACMG points: 30P and 0B. PS1_Very_Strong PS3 PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000059.4(BRCA2):​c.7876T>A​(p.Trp2626Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: "SCV000549733: Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID:33609447) indicates that this missense variant is expected to disrupt BRCA2 function.". Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W2626C) has been classified as Pathogenic. The gene BRCA2 is included in the ClinGen Criteria Specification Registry.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 7.93
• Publications: 7 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 30 ACMG points.

• PS1: Transcript NM_000059.4 (BRCA2) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000549733: Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 33609447) indicates that this missense variant is expected to disrupt BRCA2 function.
• PM1: In a hotspot region, there are 14 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 16 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 chr13-32362595-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 38125.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.985
• PP5: Variant 13-32362593-T-A is Pathogenic according to our data. Variant chr13-32362593-T-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 409541.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.7876T>A	p.Trp2626Arg	missense	Exon 17 of 27	NP_000050.3	A0A7P0T9D7
	BRCA2	NM_001432077.1		c.7876T>A	p.Trp2626Arg	missense	Exon 17 of 27	NP_001419006.1	A0A7P0T9D7
	BRCA2	NM_001406720.1		c.7876T>A	p.Trp2626Arg	missense	Exon 17 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.7876T>A	p.Trp2626Arg	missense	Exon 17 of 27	ENSP00000369497.3	P51587
	BRCA2	ENST00000544455.6	TSL:1	c.7876T>A	p.Trp2626Arg	missense	Exon 17 of 27	ENSP00000439902.1	P51587
	BRCA2	ENST00000530893.7	TSL:1	c.7507T>A	p.Trp2503Arg	missense	Exon 17 of 27	ENSP00000499438.2	A0A590UJI7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	Hereditary breast ovarian cancer syndrome (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	26
DANN	Uncertain	1.0
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Pathogenic	0.56	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
PhyloP100		7.9
PrimateAI	Pathogenic	0.79	T
PROVEAN	Uncertain	-3.7	D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.90
MutPred		0.91		Loss of ubiquitination at K2630 (P = 0.0449)
MVP		1.0
MPC		0.19
ClinPred		1.0	D
GERP RS		5.7
gMVP		0.89
Mutation Taster		=1/99	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: rs1060502459; hg19: chr13-32936730;