Variant rs180177084 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The ENST00000261584.9(PALB2):c.229del(p.Cys77ValfsTer100) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,608,822 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

PALB2
ENST00000261584.9 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 1.30

Variant links:

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]

PALB2 links:

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ACMG classification

Classification made for transcript

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 16-23636316-CA-C is Pathogenic according to our data. Variant chr16-23636316-CA-C is described in ClinVar as [Pathogenic]. Clinvar id is 126644.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23636316-CA-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PALB2	NM_024675.4 linkuse as main transcript	c.229del	p.Cys77ValfsTer100	frameshift_variant	4/13	ENST00000261584.9	NP_078951.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PALB2	ENST00000261584.9 linkuse as main transcript	c.229del	p.Cys77ValfsTer100	frameshift_variant	4/13	1	NM_024675.4	ENSP00000261584	P1

Frequencies

GnomAD3 genomes

AF:

0.00000659

AC:

AN:

151796

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1457026

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

724566

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.01e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000659

AC:

AN:

151796

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74120

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial cancer of breast

Pathogenic:4

Pathogenic, no assertion criteria provided	curation	Leiden Open Variation Database	May 13, 2019	Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Marc Tischkowitz. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 07, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 29, 2023	This sequence change creates a premature translational stop signal (p.Cys77Valfs*100) 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 present in population databases (rs180177084, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 17420451, 23341105). ClinVar contains an entry for this variant (Variation ID: 126644). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Sep 06, 2023	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 11, 2018	The variant results in a shift of the reading frame, and is therefore predicted to significantly disrupt the protein structure. Found in at least one symptomatic patient, and not found in general population data. Assessment of experimental evidence suggests this variant results in abnormal protein function. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 25, 2024	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 21113654, 26790966, 23341105, 18302019, 18628482, 20346647, 19333784, 21618343, 25099575, 19264984, 20213081, 27783279, 26411315, 17420451, 33964450, 17200672, 24136930, 17200668, 17200671) -

Hereditary cancer-predisposing syndrome

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 15, 2020	This variant deletes 1 nucleotide in exon 4 of the PALB2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been identified in 1/31356 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of PALB2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 29, 2024	The c.229delT pathogenic mutation, located in coding exon 4 of the PALB2 gene, results from a deletion of one nucleotide at nucleotide position 229, causing a translational frameshift with a predicted alternate stop codon (p.C77Vfs*100). This mutation has been seen in multiple breast cancer families and was demonstrated to result in a protein product with reduced binding to BRCA2 and deficient homologous recombination (Antoniou AC et al. N. Engl. J. Med., 2014 Aug;371:497-506; Tischkowitz M et al. Proc. Natl. Acad. Sci. U.S.A., 2007 Apr;104:6788-93). 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. -

Breast and/or ovarian cancer

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

May 25, 2020

- -

Colorectal cancer

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genetics and Molecular Pathology, SA Pathology

Oct 11, 2021

PALB2:c.229del is a deletion of a single nucleotide in exon 4 predicted to encode a frameshift of the mature mRNA with consequent premature termination of protein synthesis at codon 100 of the frameshift, or 176 (PALB2:p.(Cys77ValfsTer100)) using NP_078951.2. This is predicted to result in absent PALB2 protein due to nonsense mediated decay (NMD). If NMD is escaped, this variant is expected to encode a truncated protein. Variants of this type are widely accepted to be pathogenic (Tayoun, et al., 2018, PMID:30192042) (PVS1). PALB2:c.229del (rs180177084) is rare in population databases (gnomAD=0.00066%) (PM2). This variant has not been reported in the scientific literature in association with colon cancer. This variant has been identified in one Scottish family with multiple recurrences of breast cancer in three individuals (Tischkowitz et al., 2007, PMID: 17420451) (PS4_Supporting). Functional studies showed that this variant produced a truncated protein that had minimal BRCA2 binding capacity and defective double strand break repair by homologous recombination (Tischkowitz et al., 2007, PMID: 17420451). This variant is on record in ClinVar (Variation ID:126644) reported by multiple clinical laboratories without conflict as pathogenic in association with hereditary cancer-predisposing syndrome and familial cancer of breast. This variant is listed in HGMD as ‘disease causing mutation’ in association with the breast cancer phenotype (Accession: CD072459). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

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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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over