rs1555460315

Positions:

• chr16-23629672-ATG-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_024675.4(PALB2):​c.2480_2481del​(p.Thr827MetfsTer6) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. T827T) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PALB2 NM_024675.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 0.209

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 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-23629672-ATG-A is Pathogenic according to our data. Variant chr16-23629672-ATG-A is described in ClinVar as [Pathogenic]. Clinvar id is 430595.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23629672-ATG-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PALB2	NM_024675.4	c.2480_2481del	p.Thr827MetfsTer6	frameshift_variant	5/13	ENST00000261584.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PALB2	ENST00000261584.9	c.2480_2481del	p.Thr827MetfsTer6	frameshift_variant	5/13	1	NM_024675.4	P1

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

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 15, 2018	This deletion of two nucleotides in PALB2 is denoted c.2480_2481delCA at the cDNA level and p.Thr827MetfsX6 (T827MfsX6) at the protein level. The normal sequence, with the bases that are deleted in brackets, is AACA[delCA]TGCC. The deletion causes a frameshift which changes a Threonine to a Methionine at codon 827, and creates a premature stop codon at position 6 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. PALB2 c.2480_2481delCA has been observed in at least one individual with breast cancer (Wang 2018). We consider this variant to be pathogenic. -
Pathogenic, no assertion criteria provided	curation	Leiden Open Variation Database	Aug 25, 2018	Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Yukihide Momozawa. -

Familial cancer of breast Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 13, 2023	This sequence change creates a premature translational stop signal (p.Thr827Metfs*6) in the PALB2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PALB2 are known to be pathogenic (PMID: 17200668, 17200671, 17200672, 24136930, 25099575). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with a personal and/or family history of breast and/or ovarian cancer (PMID: 29566657). ClinVar contains an entry for this variant (Variation ID: 430595). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Sep 12, 2023	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -

Breast neoplasm Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Yang An-Suei Laboratory, Academia Sinica

-

- -

Gastric cancer Pathogenic:1

Pathogenic, no assertion criteria provided

research

Laboratory for Genotyping Development, RIKEN

Jul 01, 2021

- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 31, 2019

The c.2480_2481delCA pathogenic mutation, located in coding exon 5 of the PALB2 gene, results from a deletion of two nucleotides at nucleotide positions 2480 to 2481, causing a translational frameshift with a predicted alternate stop codon (p.T827Mfs*6). This alteration has been previously reported as a germline mutation in a cohort of 480 individuals from Taiwan with a personal and/or family history of breast and/or ovarian cancer (Wang YA et al. BMC Cancer, 2018 03;18:315). This alteration as also been reported with a carrier frequency of 0.0001 in a cohort of 12,490 male controls of Japanese ancestry (Momozawa Y et al. Nat Commun, 2018 10;9:4083). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555460315; hg19: chr16-23640993;