NM_000059.4:c.8754+3G>C

Variant names:

• chr13-32376794-G-C
• rs397508007
• NM_000059.4:c.8754+3G>C

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 14P and 1B. PS3 PM2 PP5_Very_Strong BP4

The NM_000059.4(BRCA2):​c.8754+3G>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 2/3 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: "SCV000073627: Studies have shown that this variant results in retention of 46 nucleotides of intron 21 and introduces a premature termination codon (PMID:21638052, 21769658, 23451180)." and additional evidence is available in ClinVar. The gene BRCA2 is included in the ClinGen Criteria Specification Registry.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA2 NM_000059.4 splice_region, intron
• Scores: Splicing: ADA: 0.3222
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13
• Conservation: PhyloP100: 1.54
• Publications: 10 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 13 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000073627: Studies have shown that this variant results in retention of 46 nucleotides of intron 21 and introduces a premature termination codon (PMID: 21638052, 21769658, 23451180).; SCV000186292: "In vitro RNA studies revealed that this alteration leads to monoallelic expression of a transcript retaining a part of intron 21 that is predicted to lead to a premature stop codon (Brandão RD et al. Breast Cancer Res. Treat. 2011 Oct;129(3):971-8; Thomassen M et al. Breast Cancer Res. Treat. 2012 Apr;132(3):1009-23; Colombo M et al. PLoS One, 2013 Feb;8:e57173; Ambry internal data)."; SCV002053557: Functional RNA studies have shown that this variant causes use of a cryptic splice site 46 basepairs downstream, and introduces a premature stop (PMID: 21769658, 23451180).; SCV000617475: Multiple functional studies, including minigene splicing assays and RT-PCR mRNA analyses, have demonstrated that this variant induces retention of 46 nucleotides within the transcript, resulting in a predicted frameshift and truncated protein (Brandao 2011, Thomassen 2012, Colombo 2013).
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 13-32376794-G-C is Pathogenic according to our data. Variant chr13-32376794-G-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 52668.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39). . Strength limited to SUPPORTING due to the PP5.

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.8754+3G>C		splice_region intron	N/A	NP_000050.3	A0A7P0T9D7
	BRCA2	NM_001432077.1		c.8754+3G>C		splice_region intron	N/A	NP_001419006.1	A0A7P0T9D7
	BRCA2	NM_001406720.1		c.8754+3G>C		splice_region intron	N/A	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.8754+3G>C		splice_region intron	N/A	ENSP00000369497.3	P51587
	BRCA2	ENST00000544455.6	TSL:1	c.8754+3G>C		splice_region intron	N/A	ENSP00000439902.1	P51587
	BRCA2	ENST00000530893.7	TSL:1	c.8385+3G>C		splice_region intron	N/A	ENSP00000499438.2	A0A590UJI7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
5	-	-	Breast-ovarian cancer, familial, susceptibility to, 2 (5)
4	-	-	not provided (4)
2	-	-	Hereditary breast ovarian cancer syndrome (2)
2	-	-	Hereditary cancer-predisposing syndrome (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
CADD	Benign	15
DANN	Benign	0.81
PhyloP100		1.5
Mutation Taster		=10/90	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.32
dbscSNV1_RF	Benign	0.49
Splicevardb		3.0
SpliceAI score (max)		0.75		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.75		Position offset: 43
DS_DL_spliceai		0.59		Position offset: -3

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

Other links and lift over

dbSNP: rs397508007; hg19: chr13-32950931;