NM_000059.4:c.68-7dupT

Variant names:

• chr13-32319060-A-AT
• rs276174878
• NM_000059.4:c.68-7dupT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP6_Very_Strong

The NM_000059.4(BRCA2):​c.68-7dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000292 in 1,568,270 control chromosomes in the GnomAD database, including 1 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00040 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00028 (1 hom.)
• Consequence: BRCA2 NM_000059.4 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:18
• Conservation: PhyloP100: 0.675
• Publications: 15 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):

• breast-ovarian cancer, familial, susceptibility to, 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen
• Fanconi anemia complementation group D1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen, G2P
• 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: Benign. The variant received -8 ACMG points.

• BP6: Variant 13-32319060-A-AT is Benign according to our data. Variant chr13-32319060-A-AT is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 38065.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.68-7dupT		splice_region intron	N/A	NP_000050.3
	BRCA2	NM_001432077.1		c.68-7dupT		splice_region intron	N/A	NP_001419006.1
	BRCA2	NM_001406720.1		c.68-7dupT		splice_region intron	N/A	NP_001393649.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA2	ENST00000380152.8	TSL:5 MANE Select	c.68-17_68-16insT		intron	N/A	ENSP00000369497.3
	BRCA2	ENST00000544455.6	TSL:1	c.68-17_68-16insT		intron	N/A	ENSP00000439902.1
	BRCA2	ENST00000530893.7	TSL:1	c.-302-17_-302-16insT		intron	N/A	ENSP00000499438.2

Frequencies

GnomAD3 genomes AF: 0.000399 AC: 60 AN: 150506 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00112

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000266

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000418

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000119

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000467 AC: 95 AN: 203448 AF XY: 0.000515

Gnomad AFR exome AF: 0.00122

Gnomad AMR exome AF: 0.000298

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000546

Gnomad NFE exome AF: 0.000427

Gnomad OTH exome AF: 0.000821

GnomAD4 exome AF: 0.000280 AC: 397 AN: 1417648 Hom.: 1 Cov.: 32 AF XY: 0.000264 AC XY: 186 AN XY: 705250

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

African (AFR) AF: 0.00127 AC: 41 AN: 32388

American (AMR) AF: 0.000328 AC: 14 AN: 42748

Ashkenazi Jewish (ASJ) AF: 0.0000793 AC: 2 AN: 25210

East Asian (EAS) AF: 0.000182 AC: 7 AN: 38544

South Asian (SAS) AF: 0.000603 AC: 50 AN: 82940

European-Finnish (FIN) AF: 0.0000391 AC: 2 AN: 51160

Middle Eastern (MID) AF: 0.000760 AC: 4 AN: 5260

European-Non Finnish (NFE) AF: 0.000228 AC: 246 AN: 1081004

Other (OTH) AF: 0.000531 AC: 31 AN: 58394

⚠️ 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 AF: 0.000405 AC: 61 AN: 150622 Hom.: 0 Cov.: 33 AF XY: 0.000408 AC XY: 30 AN XY: 73566

African (AFR) AF: 0.00114 AC: 47 AN: 41086

American (AMR) AF: 0.000265 AC: 4 AN: 15080

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3444

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.000418 AC: 2 AN: 4788

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10274

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000119 AC: 8 AN: 67502

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.00174 Hom.: 0

Bravo AF: 0.000423

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not provided (7)
-	-	3	Breast-ovarian cancer, familial, susceptibility to, 2 (3)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	1	BRCA2-related disorder (1)
-	-	1	Breast and/or ovarian cancer (1)
-	-	1	Familial prostate cancer (1)
-	-	1	Hereditary breast ovarian cancer syndrome (1)
-	-	1	Medulloblastoma;C0346153:Familial cancer of breast;C0376358:Prostate cancer;C1838457:Fanconi anemia complementation group D1;C2675520:Breast-ovarian cancer, familial, susceptibility to, 2;C2751641:Glioma susceptibility 3;C3150546:Pancreatic cancer, susceptibility to, 2;CN033288:Wilms tumor 1 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.68
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs276174878; hg19: chr13-32893197; COSMIC: COSV109438937;