rs515726060

Positions:

• chr16-23635492-CTGTT-C

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.1050_1053del​(p.Thr351ArgfsTer4) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,144 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)
• Consequence: PALB2 NM_024675.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:12
• Conservation: PhyloP100: 0.513

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 16-23635492-CTGTT-C is Pathogenic according to our data. Variant chr16-23635492-CTGTT-C is described in ClinVar as [Pathogenic]. Clinvar id is 126586.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23635492-CTGTT-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PALB2	NM_024675.4	c.1050_1053del	p.Thr351ArgfsTer4	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	c.1050_1053del	p.Thr351ArgfsTer4	frameshift_variant	4/13	1	NM_024675.4	ENSP00000261584	P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152144 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

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: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251298 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135848

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

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

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152144 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74344

Gnomad4 AFR AF: 0.0000241

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: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial cancer of breast Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Apr 03, 2023	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Feb 03, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 06, 2022	- -
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.Thr351Argfs*4) 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 (no rsID available, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with breast cancer and ovarian cancer (PMID: 22006311, 23977390). ClinVar contains an entry for this variant (Variation ID: 126586). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:3

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	GeneDx	Jun 07, 2021	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 (Lek et al., 2016); Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Walsh 2011, Phuah 2013, Pennington 2014, Isaacsson 2018, Fanale 2020, Yang 2020); This variant is associated with the following publications: (PMID: 22692731, 22006311, 23977390, 24240112, 24870022, 27535533, 29368341, 32854451, 31841383) -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Feb 06, 2024	- -

Hereditary cancer-predisposing syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 01, 2021	The c.1050_1053delAACA pathogenic mutation, located in coding exon 4 of the PALB2 gene, results from a deletion of 4 nucleotides at nucleotide positions 1050 to 1053, causing a translational frameshift with a predicted alternate stop codon (p.T351Rfs*4). This mutation, described as c.1050delAACA, has been identified in multiple women with breast and/or ovarian cancer (Walsh T et al. Proc. Natl. Acad. Sci. U.S.A. 2011 Nov;108:18032-7; Phuah SY et al. PLoS ONE. 2013;8:e73638; Pennington KP et al. Clin. Cancer Res. 2014 Feb;20:764-75). It was also identified in a patient with prostate cancer (Isaacsson Velho P et al. Prostate. 2018 Apr;78(5):401-407). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 31, 2023	This variant deletes 4 nucleotides 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 reported in at least two individuals and families affected with breast cancer (PMID: 23977390, 31841383) and one individual each affected with ovarian cancer (PMID: 22006311, 24240112, 26720728) and prostate cancer (PMID: 29368341). This variant has been identified in 2/251298 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	curation	Sema4, Sema4	Apr 20, 2021	- -

Familial cancer of breast;C1835817:Fanconi anemia complementation group N;C3150547:Pancreatic cancer, susceptibility to, 3 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 09, 2021

- -

Malignant tumor of breast Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Sep 14, 2020

Variant summary: PALB2 c.1050_1053delAACA (p.Thr351ArgfsX4) 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. The variant allele was found at a frequency of 8e-06 in 251298 control chromosomes (gnomAD). c.1050_1053delAACA has been reported in the literature in individuals affected with breast cancer, ovarian cancer and prostate cancer (e.g. Walsh_2011, Phuah_2013, Isaacsson Velho_2018, Yang_2020). These data indicate that the variant is likely to be associated with disease. Six ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs515726060; hg19: chr16-23646813;