ENST00000544455.6:c.-40+342G>T

Variant names:

• chr13-32315487-G-T
• rs1036870835
• ENST00000544455.6:c.-40+342G>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BP6

The ENST00000544455.6(BRCA2):​c.-40+342G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000394 in 152,226 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: 𝑓 0.000039 (0 hom., cov: 33)
• Consequence: BRCA2 ENST00000544455.6 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• Conservation: PhyloP100: 2.09
• Publications: 0 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]

ZAR1L (HGNC:37116): (zygote arrest 1 like) This gene encodes a member of the ZAR1 family that is predominantly expressed in oocytes and early embryos. The protein may function as an RNA regulator in early embryos. [provided by RefSeq, Apr 2010]

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.32).
• BP6: Variant 13-32315487-G-T is Benign according to our data. Variant chr13-32315487-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 882070.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000544455.6. 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_001432077.1		c.-40+342G>T		intron	N/A	NP_001419006.1	A0A7P0T9D7
	BRCA2	NM_000059.4	MANE Select	c.-220G>T		upstream_gene	N/A	NP_000050.3	A0A7P0T9D7
	ZAR1L	NM_001136571.2	MANE Select	c.-562C>A		upstream_gene	N/A	NP_001130043.1	A6NP61

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA2	ENST00000544455.6	TSL:1	c.-40+342G>T		intron	N/A	ENSP00000439902.1	P51587
	BRCA2	ENST00000380152.8	TSL:5 MANE Select	c.-220G>T		upstream_gene	N/A	ENSP00000369497.3	P51587
	ZAR1L	ENST00000533490.7	TSL:5 MANE Select	c.-562C>A		upstream_gene	N/A	ENSP00000437289.2	A6NP61

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152226 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 0

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152226 Hom.: 0 Cov.: 33 AF XY: 0.0000672 AC XY: 5 AN XY: 74372

African (AFR) AF: 0.00 AC: 0 AN: 41458

American (AMR) AF: 0.000196 AC: 3 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000264

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Breast-ovarian cancer, familial, susceptibility to, 2 (1)
-	1	-	Fanconi anemia complementation group D1 (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
BayesDel_noAF	Benign	-0.32
CADD	Benign	18
DANN	Benign	0.94
PhyloP100		2.1
PromoterAI		0.68	Over-expression
Mutation Taster		=290/10	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: rs1036870835; hg19: chr13-32889624;