13-32346896-G-T

Variant names:

• chr13-32346896-G-T
• rs28897743
• NM_000059.4:c.7007G>T

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PS3 PM2 PM5 PP3 PP5_Very_Strong

The NM_000059.4(BRCA2):​c.7007G>T​(p.Arg2336Leu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000689 in 1,450,868 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000277916: "In an assay testing BRCA2 function, this variant showed a functionally abnormal result (Sahu S et al. PLoS Genet . 2023 Sep;19(9):e1010940)."; SCV005888773: Published functional studies classify this variant as non-functional based on sensitivity to PARP inhibitors (PMID:37713444)". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2336C) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense, splice_region
• Scores: Splicing: ADA: 0.9992
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: 4.66
• Publications: 117 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 17 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000277916: "In an assay testing BRCA2 function, this variant showed a functionally abnormal result (Sahu S et al. PLoS Genet . 2023 Sep;19(9):e1010940)."; SCV005888773: Published functional studies classify this variant as non-functional based on sensitivity to PARP inhibitors (PMID: 37713444)
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr13-32346896-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 38077.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.
• PP5: Variant 13-32346896-G-T is Pathogenic according to our data. Variant chr13-32346896-G-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 52242.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.7007G>T	p.Arg2336Leu	missense splice_region	Exon 13 of 27	NP_000050.3	A0A7P0T9D7
	BRCA2	NM_001432077.1		c.7007G>T	p.Arg2336Leu	missense splice_region	Exon 13 of 27	NP_001419006.1	A0A7P0T9D7
	BRCA2	NM_001406720.1		c.7007G>T	p.Arg2336Leu	missense splice_region	Exon 13 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.7007G>T	p.Arg2336Leu	missense splice_region	Exon 13 of 27	ENSP00000369497.3	P51587
	BRCA2	ENST00000544455.6	TSL:1	c.7007G>T	p.Arg2336Leu	missense splice_region	Exon 13 of 27	ENSP00000439902.1	P51587
	BRCA2	ENST00000530893.7	TSL:1	c.6638G>T	p.Arg2213Leu	missense splice_region	Exon 13 of 27	ENSP00000499438.2	A0A590UJI7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.89e-7 AC: 1 AN: 1450868 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 721902

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33226

American (AMR) AF: 0.00 AC: 0 AN: 44228

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25964

East Asian (EAS) AF: 0.00 AC: 0 AN: 39410

South Asian (SAS) AF: 0.00 AC: 0 AN: 84726

European-Finnish (FIN) AF: 0.0000192 AC: 1 AN: 52154

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5700

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1105500

Other (OTH) AF: 0.00 AC: 0 AN: 59960

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.098	D
BayesDel_noAF	Benign	-0.10
CADD	Pathogenic	32
DANN	Uncertain	0.99
Eigen	Benign	-0.11
Eigen_PC	Benign	0.032
FATHMM_MKL	Uncertain	0.86	D
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.35	T
MetaSVM	Benign	-0.69	T
PhyloP100		4.7
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-0.010	N
REVEL	Uncertain	0.40
Sift	Benign	0.092	T
Sift4G	Benign	0.10	T
Vest4		0.44
MutPred		0.46		Loss of catalytic residue at R2336 (P = 0.033)
MVP		0.90
MPC		0.025
ClinPred		0.77	D
GERP RS		5.0
gMVP		0.26
Mutation Taster		=6/94	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.90
SpliceAI score (max)		0.38		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.38		Position offset: 0

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

Other links and lift over

dbSNP: rs28897743; hg19: chr13-32921033;