chr13-32398606-G-GTGAATTATA

Variant names:

• chr13-32398606-G-GTGAATTATA
• rs758307938
• NM_000059.4:c.10094_10095insGAATTATAT

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 2P and 8B. PM4 BP6_Very_Strong

The NM_000059.4(BRCA2):​c.10094_10095insGAATTATAT​(p.Val3365_Ser3366insAsnTyrIle) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000311 in 1,614,168 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. V3365V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00031 (1 hom.)
• Consequence: BRCA2 NM_000059.4 disruptive_inframe_insertion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:2 B:7
• Conservation: PhyloP100: -0.719
• Publications: 1 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 -6 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_000059.4.
• BP6: Variant 13-32398606-G-GTGAATTATA is Benign according to our data. Variant chr13-32398606-G-GTGAATTATA is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 531454.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.10094_10095insGAATTATAT	p.Val3365_Ser3366insAsnTyrIle	disruptive_inframe_insertion	Exon 27 of 27	NP_000050.3	A0A7P0T9D7
	BRCA2	NM_001432077.1		c.10094_10095insGAATTATAT	p.Val3365_Ser3366insAsnTyrIle	disruptive_inframe_insertion	Exon 27 of 27	NP_001419006.1	A0A7P0T9D7
	BRCA2	NM_001406720.1		c.10043_10044insGAATTATAT	p.Val3348_Ser3349insAsnTyrIle	disruptive_inframe_insertion	Exon 27 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.10094_10095insGAATTATAT	p.Val3365_Ser3366insAsnTyrIle	disruptive_inframe_insertion	Exon 27 of 27	ENSP00000369497.3	P51587
	BRCA2	ENST00000544455.6	TSL:1	c.10094_10095insGAATTATAT	p.Val3365_Ser3366insAsnTyrIle	disruptive_inframe_insertion	Exon 27 of 27	ENSP00000439902.1	P51587
	BRCA2	ENST00000530893.7	TSL:1	c.9725_9726insGAATTATAT	p.Val3242_Ser3243insAsnTyrIle	disruptive_inframe_insertion	Exon 27 of 27	ENSP00000499438.2	A0A590UJI7

Frequencies

GnomAD3 genomes AF: 0.000296 AC: 45 AN: 152188 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000195 AC: 49 AN: 251164 AF XY: 0.000199

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000231

Gnomad NFE exome AF: 0.000361

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000313 AC: 457 AN: 1461862 Hom.: 1 Cov.: 31 AF XY: 0.000323 AC XY: 235 AN XY: 727230

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86256

European-Finnish (FIN) AF: 0.000487 AC: 26 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000369 AC: 410 AN: 1112004

Other (OTH) AF: 0.000281 AC: 17 AN: 60394

GnomAD4 genome AF: 0.000295 AC: 45 AN: 152306 Hom.: 0 Cov.: 32 AF XY: 0.000295 AC XY: 22 AN XY: 74472

African (AFR) AF: 0.0000241 AC: 1 AN: 41570

American (AMR) AF: 0.0000654 AC: 1 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.000282 AC: 3 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000588 AC: 40 AN: 68018

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.00119 Hom.: 0

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.72
Mutation Taster		=84/16	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs758307938; hg19: chr13-32972743; COSMIC: COSV105931948;