rs80359698

Variant names:

• chr13-32363427-ATGGCAGACTGACAGT-A
• rs80359698
• NM_000059.4:c.8229_8243delCAGACTGACAGTTGG

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PS3 PM1 PM4 PP3 PP5_Very_Strong

The NM_000059.4(BRCA2):​c.8229_8243delCAGACTGACAGTTGG​(p.Arg2744_Gly2748del) variant causes a disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000887933: The variant results in the in-frame deletion of five amino acids in the DNA/DSS1 binding domain of the BRCA2 protein, which has been characterized as evolutionarily highly conserved and functionally significant (PMID:14757868 (2004)).". Synonymous variant affecting the same amino acid position (i.e. G2743G) has been classified as Likely benign. The gene BRCA2 is included in the ClinGen Criteria Specification Registry.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA2 NM_000059.4 disruptive_inframe_deletion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5 U:3
• Conservation: PhyloP100: 7.78
• Publications: 3 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 17 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000887933: The variant results in the in-frame deletion of five amino acids in the DNA/DSS1 binding domain of the BRCA2 protein, which has been characterized as evolutionarily highly conserved and functionally significant (PMID: 14757868 (2004)).
• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 17 benign, 21 uncertain in NM_000059.4
• PM4: Nonframeshift variant in NON repetitive region in NM_000059.4.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 13-32363427-ATGGCAGACTGACAGT-A is Pathogenic according to our data. Variant chr13-32363427-ATGGCAGACTGACAGT-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 52531.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.8229_8243delCAGACTGACAGTTGG	p.Arg2744_Gly2748del	disruptive_inframe_deletion	Exon 18 of 27	NP_000050.3	A0A7P0T9D7
	BRCA2	NM_001432077.1		c.8229_8243delCAGACTGACAGTTGG	p.Arg2744_Gly2748del	disruptive_inframe_deletion	Exon 18 of 27	NP_001419006.1	A0A7P0T9D7
	BRCA2	NM_001406720.1		c.8229_8243delCAGACTGACAGTTGG	p.Arg2744_Gly2748del	disruptive_inframe_deletion	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.8229_8243delCAGACTGACAGTTGG	p.Arg2744_Gly2748del	disruptive_inframe_deletion	Exon 18 of 27	ENSP00000369497.3	P51587
	BRCA2	ENST00000544455.6	TSL:1	c.8229_8243delCAGACTGACAGTTGG	p.Arg2744_Gly2748del	disruptive_inframe_deletion	Exon 18 of 27	ENSP00000439902.1	P51587
	BRCA2	ENST00000530893.7	TSL:1	c.7860_7874delCAGACTGACAGTTGG	p.Arg2621_Gly2625del	disruptive_inframe_deletion	Exon 18 of 27	ENSP00000499438.2	A0A590UJI7

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	1	-	Breast-ovarian cancer, familial, susceptibility to, 2 (2)
-	1	-	Breast and/or ovarian cancer (1)
1	-	-	Familial cancer of breast (1)
1	-	-	Hereditary breast ovarian cancer syndrome (1)
1	-	-	Hereditary cancer-predisposing syndrome (1)
1	-	-	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.8
Mutation Taster		=83/117	disease causing (ClinVar)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs80359698; hg19: chr13-32937564;