rs180177092

chr16-23635787-TAG-T

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.757_758del(p.Leu253IlefsTer3) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,850 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. L253L) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: PALB2 NM_024675.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:24 O:2
• Conservation: PhyloP100: 0.0860

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 16-23635787-TAG-T is Pathogenic according to our data. Variant chr16-23635787-TAG-T is described in ClinVar as [Pathogenic]. Clinvar id is 126768.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23635787-TAG-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PALB2	NM_024675.4	c.757_758del	p.Leu253IlefsTer3	frameshift_variant	4/13	ENST00000261584.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PALB2	ENST00000261584.9	c.757_758del	p.Leu253IlefsTer3	frameshift_variant	4/13	1	NM_024675.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251366 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135880

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: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461850 Hom.: 0 AF XY: 0.00000413 AC XY: 3 AN XY: 727234

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: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:24 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial cancer of breast Pathogenic:9 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 31, 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	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 03, 2018	Variant summary: PALB2 c.757_758delCT (p.Leu253IlefsX3) 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.1240C>T/p.Arg414X, c.2167_2168delAT/p.Met723fsX21). The variant allele was found at a frequency of 8.2e-06 in 123596 control chromosomes. c.757_758delCT has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer in heterozygous state and one individual with Fanconi anemia in compound heterozygous state (Walsh_2011, Casedei_2011, Tung_2015). These data indicate that the variant is very likely to be associated with disease. Seven ClinVar submissions from other clinical diagnostic laboratories (evaluation after 2014) cite the variant as "pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jul 21, 2023	Criteria applied: PVS1,PS4,PM2_SUP -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 04, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	This sequence change creates a premature translational stop signal (p.Leu253Ilefs*3) 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 (rs180177092, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with breast cancer and breast cancer and/or ovarian cancer and Fanconi anemia (PMID: 17200671, 21285249, 22006311, 26845104, 26898890). ClinVar contains an entry for this variant (Variation ID: 126768). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Aug 18, 2022	PVS1, PM2, PS4_Strong -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	May 12, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Oct 01, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Nov 09, 2016	- -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant interpretted as Pathogenic and reported on 02-05-2020 by Lab or GTR ID Credit Valley Hospital Department of Laboratory Medicine. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

not provided Pathogenic:5

Pathogenic, no assertion criteria provided	curation	Leiden Open Variation Database	May 13, 2019	Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitters to LOVD: Arleen D. Auerbach, LOVD-team, but with Curator vacancy, Marc Tischkowitz. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 23, 2021	This frameshift variant causes the premature termination of PALB2 protein synthesis. In addition, it has been reported in individuals with breast or endometrial cancer in the published literature (PMIDs: 26898890 (2016), 26681312 (2015) and 21285249 (2011)). Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2022	PALB2: PVS1, PM2 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 31, 2020	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 a significant frequency in large population cohorts (Lek 2016); Observed in several individuals with personal and/or family history of PALB2-related cancers (Jones 2009, Casadei 2011, Tung 2014, Caminsky 2016, Shirts 2016); This variant is associated with the following publications: (PMID: 23935381, 29753700, 26681312, 29706558, 19264984, 22006311, 21285249, 24240112, 25186627, 25099575, 21165770, 26898890, 26845104, 28152038, 17200671, 31159747) -

Hereditary cancer-predisposing syndrome Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 21, 2022	This variant deletes 2 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. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least 10 individuals affected with breast, peritoneal and endometrial cancer and one unaffected individual (PMID: 21285249, 22006311, 23935381, 25186627, 26681312, 26845104, 33471991; Leiden Open Variation Database DB-ID PALB2_000005) and an individual affected with medulloblastoma (PMID: 29753700). This variant also has been reported in trans with another pathogenic PALB2 variant in an individual affected with biallelic Fanconi anemia (PMID: 17200671). This variant has been identified in 2/251366 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	University of Washington Department of Laboratory Medicine, University of Washington	Nov 20, 2015	- -
Pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Jun 23, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneKor MSA	Jan 01, 2020	This mutation is a 2 nucleotide deletion in exon 4 of the PALB2 gene. This result in a frameshift and the creation of a premature stop codon three amino acid residues later. This mutation has been described in international literature (https://grenada.lumc.nl; http://rgd.mcw.edu). -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	May 17, 2022	The c.757_758delCT pathogenic mutation, located in coding exon 4 of the PALB2 gene, results from a deletion of two nucleotides at nucleotide positions 757 to 758, causing a translational frameshift with a predicted alternate stop codon (p.L253Ifs*3). This mutation has been reported in both Fanconi anemia type-N (FA-N) and familial breast cancer cohorts (Reid S et al. Nat. Genet. 2007 Feb;39:162-4; Tischkowitz M et al. Proc. Natl. Acad. Sci. USA. 2007 Apr;104:6788-93; Casadei S et al. Cancer Res. 2011 Mar;71:2222-9; Antoniou AC et al. N. Engl. J. Med. 2014 Aug;371:497-506; Tung N et al. Cancer. 2015 Jan;121:25-33; Susswein LR et al. Genet. Med. 2016 Aug;18:823-32). Another study reported this mutation in a woman with peritoneal carcinoma and a family history significant for breast and/or ovarian cancer (Walsh T et al. Proc. Natl. Acad. Sci. USA. 2011 Nov;108:18032-7). It was also seen in a medulloblastoma cohort (Waszak SM et al. Lancet Oncol. 2018 06;19(6):785-798). In addition to the information 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. -

Fanconi anemia complementation group N Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 06, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 04, 2015	- -

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

Dec 27, 2021

- -

Breast and/or ovarian cancer Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Jun 09, 2023

- -

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Feb 05, 2023

_x000D_ Criteria applied: PVS1, PS4, PM2_SUP -

Malignant tumor of breast;C1835817:Fanconi anemia complementation group N Other:1

not provided, no classification provided

phenotyping only

GenomeConnect - Invitae Patient Insights Network

-

Variant interpreted as Pathogenic and reported on 05-28-2015 by Ambry Genetics. 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. -

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: rs180177092; hg19: chr16-23647108;