Variant rs730881869 details in Genebe, Genetics Data Aggregator

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 16-23626255-TAA-T is Pathogenic according to our data. Variant chr16-23626255-TAA-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 182742.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PALB2	NM_024675.4 linkuse as main transcript	c.2727_2728del	p.Thr911LeufsTer16	frameshift_variant	7/13	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.2727_2728del	p.Thr911LeufsTer16	frameshift_variant	7/13	1	NM_024675.4	ENSP00000261584	P1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

1

AN:

152168

Hom.:

0

Cov.:

32

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

GnomAD3 exomes

AF:

0.00000398

AC:

1

AN:

251482

Hom.:

0

AF XY:

0.00

AC XY:

0

AN XY:

135920

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

3

AN:

1461862

Hom.:

0

AF XY:

0.00000275

AC XY:

2

AN XY:

727232

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:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

1

AN:

152168

Hom.:

0

Cov.:

32

AF XY:

0.0000135

AC XY:

1

AN XY:

74338

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

Bravo

AF:

0.00000756

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial cancer of breast

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 03, 2024	This sequence change creates a premature translational stop signal (p.Thr911Leufs*16) 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 (rs730881869, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 26681312). ClinVar contains an entry for this variant (Variation ID: 182742). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Apr 27, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Apr 27, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Feb 24, 2018	This c.2727_2728delTT (p.Thr911Leufs*16) frameshift variant in the PALB2 gene is predicted to introduce a premature translation termination codon. This variant has been reported in two unrelated breast cancer patients (PMID 26681312 and 28724667). Moreover, four independent genetic diagnostic laboratories have categorized this variant as pathogenic/likely pathogenic (ClinVar database). Mono-allelic loss of function variants in the PALB2 gene have been associated with susceptibility to breast cancer and pancreatic cancer. Bi-allelic loss of function variants in this gene are associated with Fanconi anemia, complementation group N (OMIM 610832). This variant in the PALB2 gene is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Sep 13, 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	Jul 11, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 02, 2023	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; Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Lowery et al., 2018; Sun et al., 2017); This variant is associated with the following publications: (PMID: 28724667, 26681312, 29506128, 31447099, 32546565, 29922827, 33804961) -

Hereditary cancer-predisposing syndrome

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 04, 2023	This variant deletes 2 nucleotides in exon 7 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 reported in individuals affected with breast cancer (PMID: 26681312, 28724667, 31768816) and pancreatic cancer (PMID: 29506128). This variant has been identified in 1/251482 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	Dec 29, 2021	The c.2727_2728delTT pathogenic mutation, located in coding exon 7 of the PALB2 gene, results from a deletion of two nucleotides at nucleotide positions 2727 to 2728, causing a translational frameshift with a predicted alternate stop codon (p.T911Lfs*16). This alteration has been identified in individuals diagnosed with breast cancer and a pancreatic exocrine neoplasm (Sun J et al. Clin Cancer Res, 2017 Oct;23:6113-6119; Lowery MA et al. J Natl Cancer Inst, 2018 10;110:1067-1074). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. -

PALB2-related disorder

Pathogenic:1Other:1

Pathogenic, no assertion criteria provided	clinical testing	PreventionGenetics, part of Exact Sciences	Mar 01, 2024	The PALB2 c.2727_2728delTT variant is predicted to result in a frameshift and premature protein termination (p.Thr911Leufs*16). This variant has been reported in individuals with breast cancer (Supplementary Table S3, Sun et al. 2017. PubMed ID: 28724667), exocrine pancreatic neoplasm (Lowery et al. 2018. PubMed ID: 29506128) and ovarian cancer (Supplementary Table 3, Song et al. 2021. PubMed ID: 32546565). This variant was identified in an individual referred for next-generation cancer panel testing and was classified as pathogenic (Supplementary Table S1, Susswein et al. 2016. PubMed ID: 26681312). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/182742). Frameshift variants in PALB2 are expected to be pathogenic. This variant is interpreted as pathogenic. -
not provided, no classification provided	phenotyping only	GenomeConnect - Invitae Patient Insights Network	-	Variant interpreted as Pathogenic and reported on 12-07-2017 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

Familial cancer of breast;C1835817:Fanconi anemia complementation group N;C3150547:Pancreatic cancer, susceptibility to, 3

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 27, 2021

- -

Gastric cancer

Pathogenic:1

Pathogenic, no assertion criteria provided

research

Laboratory for Genotyping Development, RIKEN

Jul 01, 2021

- -

Hereditary breast ovarian cancer syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Apr 12, 2019

Variant summary: PALB2 c.2727_2728delTT (p.Thr911LeufsX16) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (eg. c.2920_2921delAA, p.Lys974fsX5; c.3113G>A, p.Trp1038X). The variant allele was found at a frequency of 4.1e-06 in 246270 control chromosomes. c.2727_2728delTT has been reported in the literature in individuals affected with breast and pancreatic cancer (Lowery_2018, Sun_2017, Susswein_2015). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

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Splicing

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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.

rs730881869

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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