NM_000059.4:c.1909+22delT

Variant names:

• chr13-32333398-CT-C
• rs276174816
• NM_000059.4:c.1909+22delT

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP6

The NM_000059.4(BRCA2):​c.1909+22delT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0397 in 964,172 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00065 (0 hom., cov: 32)
  • Exomes 𝑓: 0.047 (0 hom.)
• Consequence: BRCA2 NM_000059.4 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:11
• Conservation: PhyloP100: 0.591
• Publications: 14 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_benign. The variant received -1 ACMG points.

• BP6: Variant 13-32333398-CT-C is Benign according to our data. Variant chr13-32333398-CT-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 132782.

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.1909+22delT		intron	N/A	NP_000050.3	A0A7P0T9D7
	BRCA2	NM_001432077.1		c.1909+22delT		intron	N/A	NP_001419006.1	A0A7P0T9D7
	BRCA2	NM_001406720.1		c.1909+22delT		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.1909+12delT		intron	N/A	ENSP00000369497.3	P51587
	BRCA2	ENST00000544455.6	TSL:1	c.1909+12delT		intron	N/A	ENSP00000439902.1	P51587
	BRCA2	ENST00000530893.7	TSL:1	c.1540+12delT		intron	N/A	ENSP00000499438.2	A0A590UJI7

Frequencies

GnomAD3 genomes AF: 0.000644 AC: 94 AN: 145908 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000250

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00123

Gnomad ASJ AF: 0.000296

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00372

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000440

Gnomad OTH AF: 0.00100

GnomAD2 exomes AF: 0.113 AC: 9023 AN: 79632 AF XY: 0.113

Gnomad AFR exome AF: 0.0851

Gnomad AMR exome AF: 0.144

Gnomad ASJ exome AF: 0.149

Gnomad EAS exome AF: 0.111

Gnomad FIN exome AF: 0.0513

Gnomad NFE exome AF: 0.116

Gnomad OTH exome AF: 0.123

GnomAD4 exome AF: 0.0467 AC: 38212 AN: 818208 Hom.: 0 Cov.: 29 AF XY: 0.0473 AC XY: 18977 AN XY: 401578

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

African (AFR) AF: 0.0522 AC: 988 AN: 18916

American (AMR) AF: 0.0770 AC: 1935 AN: 25124

Ashkenazi Jewish (ASJ) AF: 0.0628 AC: 834 AN: 13286

East Asian (EAS) AF: 0.0546 AC: 1040 AN: 19040

South Asian (SAS) AF: 0.0624 AC: 2630 AN: 42170

European-Finnish (FIN) AF: 0.0522 AC: 1401 AN: 26814

Middle Eastern (MID) AF: 0.0346 AC: 127 AN: 3672

European-Non Finnish (NFE) AF: 0.0435 AC: 27685 AN: 636880

Other (OTH) AF: 0.0487 AC: 1572 AN: 32306

⚠️ 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: 0.000651 AC: 95 AN: 145964 Hom.: 0 Cov.: 32 AF XY: 0.000719 AC XY: 51 AN XY: 70948

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

African (AFR) AF: 0.000275 AC: 11 AN: 40036

American (AMR) AF: 0.00123 AC: 18 AN: 14604

Ashkenazi Jewish (ASJ) AF: 0.000296 AC: 1 AN: 3384

East Asian (EAS) AF: 0.00 AC: 0 AN: 5010

South Asian (SAS) AF: 0.00 AC: 0 AN: 4636

European-Finnish (FIN) AF: 0.00372 AC: 34 AN: 9150

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 278

European-Non Finnish (NFE) AF: 0.000440 AC: 29 AN: 65952

Other (OTH) AF: 0.000994 AC: 2 AN: 2012

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0672 Hom.: 0

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	3	Breast-ovarian cancer, familial, susceptibility to, 2 (4)
-	1	2	not specified (3)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	2	not provided (2)
-	-	1	BRCA2-related disorder (1)
-	-	1	Hereditary breast ovarian cancer syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.59
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: rs276174816; hg19: chr13-32907535; COSMIC: COSV66463516; COSMIC: COSV66463516;