rs1060502398

Variant names:

• chr13-32370484-TATC-T
• rs1060502398
• NM_000059.4:c.8418_8420delATC

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PM2 PM4_Supporting

The NM_000059.4(BRCA2):​c.8418_8420delATC​(p.Ser2807del) variant causes a disruptive inframe deletion change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. S2806S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA2 NM_000059.4 disruptive_inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 6.06
• 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):

• 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: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 19 benign, 31 uncertain in NM_000059.4
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000059.4. Strenght limited to Supporting due to length of the change: 1aa.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA2	NM_000059.4	MANE Select	c.8418_8420delATC	p.Ser2807del	disruptive_inframe_deletion	Exon 19 of 27	NP_000050.3
	BRCA2	NM_001432077.1		c.8418_8420delATC	p.Ser2807del	disruptive_inframe_deletion	Exon 19 of 27	NP_001419006.1
	BRCA2	NM_001406720.1		c.8418_8420delATC	p.Ser2807del	disruptive_inframe_deletion	Exon 19 of 27	NP_001393649.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA2	ENST00000380152.8	TSL:5 MANE Select	c.8418_8420delATC	p.Ser2807del	disruptive_inframe_deletion	Exon 19 of 27	ENSP00000369497.3
	BRCA2	ENST00000544455.6	TSL:1	c.8418_8420delATC	p.Ser2807del	disruptive_inframe_deletion	Exon 19 of 27	ENSP00000439902.1
	BRCA2	ENST00000530893.7	TSL:1	c.8049_8051delATC	p.Ser2684del	disruptive_inframe_deletion	Exon 19 of 27	ENSP00000499438.2

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.26		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.26		Position offset: 16

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

Other links and lift over

dbSNP: rs1060502398; hg19: chr13-32944621;