rs786203892

chr16-23626231-CTTACCT-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1_Moderate PP5_Very_Strong

The NM_024675.4(PALB2):c.2747_2748+4del variant causes a splice donor, splice donor region, coding sequence, intron change. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. E916E) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: PALB2 NM_024675.4 splice_donor, splice_donor_region, coding_sequence, intron
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 5.37

Genes affected

PALB2 (HGNC:26144): (partner and localizer of BRCA2) This gene encodes a protein that may function in tumor suppression. This protein binds to and colocalizes with the breast cancer 2 early onset protein (BRCA2) in nuclear foci and likely permits the stable intranuclear localization and accumulation of BRCA2. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PVS1: Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.04521202 fraction of the gene. Cryptic splice site detected, with MaxEntScore 6.7, offset of 4, new splice context is: cagGTggga. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PP5: Variant 16-23626231-CTTACCT-C is Pathogenic according to our data. Variant chr16-23626231-CTTACCT-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 187647.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23626231-CTTACCT-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PALB2	NM_024675.4	c.2747_2748+4del		splice_donor_variant, splice_donor_region_variant, coding_sequence_variant, intron_variant	7/13	ENST00000261584.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PALB2	ENST00000261584.9	c.2747_2748+4del		splice_donor_variant, splice_donor_region_variant, coding_sequence_variant, intron_variant	7/13	1	NM_024675.4	P1

Frequencies

GnomAD3 genomes Cov.: 31

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

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, no assertion criteria provided	curation	Leiden Open Variation Database	Dec 23, 2019	Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Florentia Fostira. -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneKor MSA	Jan 01, 2020	This is variation is a 6 nucleotide deletion. The deletion expands to the donor splice site in intron 7 of the PALB2. This mutation seems to activate a cryptic donor splice site, causing frameshift at codon 196. This results in a disrupted protein product. Truncating mutations in PALB2 are known to be pathogenic. The mutation database ClinVar contains entries for this variant (Variation ID: 187647). -

Familial cancer of breast Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Sep 13, 2023	This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in PALB2 are known to be pathogenic (PMID: 17200668, 24136930, 25099575). This variant has not been reported in the literature in individuals with PALB2-related conditions. ClinVar contains an entry for this variant (Variation ID: 187647). This variant results in the deletion of part of exon 7 (c.2747_2748+4del) of the PALB2 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 16, 2023

The c.2747_2748+4delAGGTAA mutation is a deletion beginning in coding exon 7 of the PALB2 gene and extending 4 nucleotides into intron 7. This results in the deletion of a total of 6 nucleotides, including the last 2 nucleotides of coding exon 7 and the splice donor site of intron 7. The deletion within coding exon 7 is predicted to cause a translational frameshift with an alternate stop codon. Since both frameshifts and alterations that disrupt the canonical splice site are expected to cause an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay, this alteration is classified as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs786203892; hg19: chr16-23637552;