chr13-32326282-G-A

Variant names:

• chr13-32326282-G-A
• rs80359790
• NM_000059.4:c.516G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PS3 PM2 PP3 PP5

The NM_000059.4(BRCA2):​c.516G>A​(p.Lys172Lys) variant causes a splice region, synonymous change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV004848359: Exon trapping and RT-PCR analysis showed that this variant results in skipping of exon 6 and of exon 5 and 6. The skipping results in a frameshift and a premature termination at codon 154 (skipping of exon 5 and 6) or codon 168 (skipping of exon 6), which most likely will result in nonsense-mediated mRNA decay (NMD) (Hansen 2009 PubMed: 19267246).; SCV004833253: Patient RNA analysis and mini gene assay showed abnormal splicing that led to nonsense-mediated decay (PMID:19267246).; SCV001185564: Splicing assays have shown this variant to result in nonsense-mediated decay prone transcripts that lack coding exons 4 and 5 (Ambry internal data; Hansen TV et al. Breast Cancer Res. Treat. 2010 Feb;119:547-50).".

• Frequency: Genomes: not found (cov: 33)
• Consequence: BRCA2 NM_000059.4 splice_region, synonymous
• Scores: Splicing: ADA: 0.9996
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:10 U:3
• Conservation: PhyloP100: 3.71
• Publications: 16 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: Likely_pathogenic. The variant received 8 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV004848359: Exon trapping and RT-PCR analysis showed that this variant results in skipping of exon 6 and of exon 5 and 6. The skipping results in a frameshift and a premature termination at codon 154 (skipping of exon 5 and 6) or codon 168 (skipping of exon 6), which most likely will result in nonsense-mediated mRNA decay (NMD) (Hansen 2009 PubMed: 19267246).; SCV004833253: Patient RNA analysis and mini gene assay showed abnormal splicing that led to nonsense-mediated decay (PMID: 19267246).; SCV001185564: Splicing assays have shown this variant to result in nonsense-mediated decay prone transcripts that lack coding exons 4 and 5 (Ambry internal data; Hansen TV et al. Breast Cancer Res. Treat. 2010 Feb;119:547-50).
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 13-32326282-G-A is Pathogenic according to our data. Variant chr13-32326282-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 51795.

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.516G>A	p.Lys172Lys	splice_region synonymous	Exon 6 of 27	NP_000050.3	A0A7P0T9D7
	BRCA2	NM_001432077.1		c.516G>A	p.Lys172Lys	splice_region synonymous	Exon 6 of 27	NP_001419006.1	A0A7P0T9D7
	BRCA2	NM_001406720.1		c.516G>A	p.Lys172Lys	splice_region synonymous	Exon 6 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.516G>A	p.Lys172Lys	splice_region synonymous	Exon 6 of 27	ENSP00000369497.3	P51587
	BRCA2	ENST00000544455.6	TSL:1	c.516G>A	p.Lys172Lys	splice_region synonymous	Exon 6 of 27	ENSP00000439902.1	P51587
	BRCA2	ENST00000530893.7	TSL:1	c.147G>A	p.Lys49Lys	splice_region synonymous	Exon 6 of 27	ENSP00000499438.2	A0A590UJI7

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	23
DANN	Benign	0.82
PhyloP100		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=12/88	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
Splicevardb		3.0
SpliceAI score (max)		0.84		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.84		Position offset: 0

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

Other links and lift over

dbSNP: rs80359790; hg19: chr13-32900419;