chr13-32326613-G-A

Variant names:

• chr13-32326613-G-A
• rs80358871
• NM_000059.4:c.631G>A

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PS3 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000059.4(BRCA2):​c.631G>A​(p.Val211Ile) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000702 in 1,424,234 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000591699: "Indeed, functional studies have shown that the variant altered the natural splice sites leading to exon skipping due to modification of the sequence of the 5' splice site (Pensabene 2009, Gaildrat 2012)."; SCV000275759: Functional studies have demonstrated that the c.631G>A alteration leads to the skipping of coding exon 6, leading to a frameshift and alternate stop in coding exon 8 (Ambry internal data; Pensabene M et al. Ann. Oncol. 2009 May;20(5):874-8; Colombo M et al. Ann. Oncol. 2009 Jun;20(6):1143-4). Functional studies have also demonstrated that the c.7008-2A>T alteration leads to multiple transcripts of different lengths, most of which lead to a frameshift and alternate stop codon (Ambry internal data; Pensabene M et al. Ann. Oncol. 2009 May;20(5):874-8; Colombo M et al. Ann. Oncol. 2009 Jun;20(6):1143-4; Houdayer C et al. Hum. Mutat. 2012 Aug;33(8):1228-38; Colombo M et al. PLoS ONE 2013;8(2):e57173).; SCV000683772: RNA studies using patient-derived cells (PMID 19179552, 19423647, 23451180) and a mini-gene splicing assay (PMID:22962691) have demonstrated that this variant causes a complete skipping of exon 7 and premature truncation.; SCV004220498: "In functional studies, this variant has been shown to disrupt splicing and lead to exon skipping and premature truncation of the protein (PMIDs: 30883759 (2019), 23451180 (2013), 22962691 (2012), 19423647 (2009))."; SCV000694962: Several publications report experimental evidence that this variant disrupts mRNA splicing, leading to skipping or shortening of exon 7 (e.g., Pensabene_2009, Colombo_2009, Gaildrat_2012). PMID:22009639, 23451180, 12960223, 22962691, 19542536, 19179552, 19423647, 27062684, 27125725; SCV001577033: Studies have shown that this missense change alters mRNA splicing and is expected to lead to the loss of protein expression (PMID:19179552, 22962691, 23451180; Invitae).". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V211A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:15
• Conservation: PhyloP100: 3.91
• Publications: 43 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: Pathogenic. The variant received 20 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000591699: "Indeed, functional studies have shown that the variant altered the natural splice sites leading to exon skipping due to modification of the sequence of the 5' splice site (Pensabene 2009, Gaildrat 2012)."; SCV000275759: Functional studies have demonstrated that the c.631G>A alteration leads to the skipping of coding exon 6, leading to a frameshift and alternate stop in coding exon 8 (Ambry internal data; Pensabene M et al. Ann. Oncol. 2009 May;20(5):874-8; Colombo M et al. Ann. Oncol. 2009 Jun;20(6):1143-4). Functional studies have also demonstrated that the c.7008-2A>T alteration leads to multiple transcripts of different lengths, most of which lead to a frameshift and alternate stop codon (Ambry internal data; Pensabene M et al. Ann. Oncol. 2009 May;20(5):874-8; Colombo M et al. Ann. Oncol. 2009 Jun;20(6):1143-4; Houdayer C et al. Hum. Mutat. 2012 Aug;33(8):1228-38; Colombo M et al. PLoS ONE 2013;8(2):e57173).; SCV000683772: RNA studies using patient-derived cells (PMID 19179552, 19423647, 23451180) and a mini-gene splicing assay (PMID: 22962691) have demonstrated that this variant causes a complete skipping of exon 7 and premature truncation.; SCV004220498: "In functional studies, this variant has been shown to disrupt splicing and lead to exon skipping and premature truncation of the protein (PMIDs: 30883759 (2019), 23451180 (2013), 22962691 (2012), 19423647 (2009))."; SCV000694962: Several publications report experimental evidence that this variant disrupts mRNA splicing, leading to skipping or shortening of exon 7 (e.g., Pensabene_2009, Colombo_2009, Gaildrat_2012). PMID: 22009639, 23451180, 12960223, 22962691, 19542536, 19179552, 19423647, 27062684, 27125725; SCV001577033: Studies have shown that this missense change alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 19179552, 22962691, 23451180; Invitae).
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr13-32326613-G-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 38035.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 13-32326613-G-A is Pathogenic according to our data. Variant chr13-32326613-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 52058.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.631G>A	p.Val211Ile	missense splice_region	Exon 7 of 27	NP_000050.3	A0A7P0T9D7
	BRCA2	NM_001432077.1		c.631G>A	p.Val211Ile	missense splice_region	Exon 7 of 27	NP_001419006.1	A0A7P0T9D7
	BRCA2	NM_001406720.1		c.631G>A	p.Val211Ile	missense splice_region	Exon 7 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.631G>A	p.Val211Ile	missense splice_region	Exon 7 of 27	ENSP00000369497.3	P51587
	BRCA2	ENST00000544455.6	TSL:1	c.631G>A	p.Val211Ile	missense splice_region	Exon 7 of 27	ENSP00000439902.1	P51587
	BRCA2	ENST00000530893.7	TSL:1	c.262G>A	p.Val88Ile	missense splice_region	Exon 7 of 27	ENSP00000499438.2	A0A590UJI7

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.02e-7 AC: 1 AN: 1424234 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 710436

African (AFR) AF: 0.00 AC: 0 AN: 32566

American (AMR) AF: 0.00 AC: 0 AN: 44382

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25890

East Asian (EAS) AF: 0.00 AC: 0 AN: 39434

South Asian (SAS) AF: 0.00 AC: 0 AN: 85132

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53380

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5694

European-Non Finnish (NFE) AF: 9.27e-7 AC: 1 AN: 1078576

Other (OTH) AF: 0.00 AC: 0 AN: 59180

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Uncertain	0.073	D
BayesDel_noAF	Benign	-0.13
CADD	Pathogenic	26
DANN	Uncertain	1.0
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.92	D
M_CAP	Pathogenic	0.32	D
MetaRNN	Benign	0.34	T
MetaSVM	Benign	-0.83	T
PhyloP100		3.9
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.25	N
REVEL	Benign	0.18
Sift	Benign	0.036	D
Sift4G	Uncertain	0.0080	D
Vest4		0.30
MutPred		0.21		Loss of glycosylation at S206 (P = 0.1112)
MVP		0.82
MPC		0.092
ClinPred		0.92	D
GERP RS		5.7
gMVP		0.19
Mutation Taster		=16/84	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)		0.81		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.81		Position offset: 0

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

Other links and lift over

dbSNP: rs80358871; hg19: chr13-32900750;