rs587776527

chr16-23607958-G-Achr16-23607958-G-Cchr16-23607958-G-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_024675.4(PALB2):c.3256C>T(p.Arg1086Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000178 in 1,461,816 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R1086R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: PALB2 NM_024675.4 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:21 O:1
• Conservation: PhyloP100: 1.64

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]

(HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 68 pathogenic variants in the truncated region.
• PP5: Variant 16-23607958-G-A is Pathogenic according to our data. Variant chr16-23607958-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 126729.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23607958-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PALB2	NM_024675.4	c.3256C>T	p.Arg1086Ter	stop_gained	12/13	ENST00000261584.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PALB2	ENST00000261584.9	c.3256C>T	p.Arg1086Ter	stop_gained	12/13	1	NM_024675.4	P1
	ENST00000561764.1	n.185+575G>A		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000199 AC: 5 AN: 251482 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135920

Gnomad AFR exome AF: 0.0000615

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: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000178 AC: 26 AN: 1461816 Hom.: 0 Cov.: 31 AF XY: 0.0000151 AC XY: 11 AN XY: 727200

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000216

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:21 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial cancer of breast Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jul 23, 2023	- -
Likely pathogenic, criteria provided, single submitter	case-control	Cancer Genetics Laboratory, Peter MacCallum Cancer Centre	Jun 01, 2015	- -
Pathogenic, no assertion criteria provided	research	deCODE genetics, Amgen	Jul 21, 2023	The variant NM_024675.4:c.3256C>T (chr16:23607958) in PALB2 was detected in 33 heterozygotes out of 58K WGS Icelanders (MAF= 0,028%). Following imputation in a set of 166K Icelanders (71 imputed heterozygotes) we observed an association with breast cancer using 6908 cases and 292623 controls (OR= 5.57, P= 6.93e-05). This variant has been reported in ClinVar previously as pathogenic/likely pathogenic. Based on ACMG criteria (PVS1, PS4, PP5) this variant classifies as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Jan 27, 2023	ACMG classification criteria: PVS1 very strong, PS4 strong, PM2 moderated -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Sep 14, 2023	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 21, 2024	This sequence change creates a premature translational stop signal (p.Arg1086*) 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 (rs587776527, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with pancreatic cancer (PMID: 19264984, 23561644, 25356972, 26283626, 26315354, 26845104). ClinVar contains an entry for this variant (Variation ID: 126729). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 02, 2023	This nonsense variant causes the premature termination of PALB2 protein synthesis. The frequency of this variant in the general population, 0.000035 (4/113760 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in individuals with breast cancer (PMID: 26845104 (2016), 28779002 (2017), 29752822 (2018), 30720863 (2019), 31841383 (2020)), ovarian cancer (PMID: 26315354 (2015), 26720728 (2016)), prostate cancer (PMID: 32853339 (2021)), and pancreatic cancer (PMID: 23561644 (2013). Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 17, 2023	Nonsense 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); Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Jones et al., 2009; Grant et al., 2013; Ramus et al., 2015; Norquist et al., 2016; Zhang et al., 2017); This variant is associated with the following publications: (PMID: 26283626, 26845104, 23935836, 28779002, 29922827, 19264984, 23561644, 25525159, 25356972, 21165770, 26315354, 24870022, 26720728, 26546047, 26681312, 28495237, 28736627, 20888394, 28825143, 29752822, 28724667, 30720863, 31263054, 31768816, 28418444, 31921681, 32068069, 32339256, 34426522, 32546565, 32566746, 30982232, 33169439, 32853339, 31619740, 34113003, 34917121, 33471991, 36278678) -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Feb 06, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -

Hereditary cancer-predisposing syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 07, 2022	This variant changes 1 nucleotide in exon 12 of the PALB2 gene, creating a 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: 26283626, 28724667, 29752822, 32566746), ovarian cancer (PMID 26720728) and pancreatic cancer (PMID: 19264984, 23561644, 25356972). This variant also has been detected in a breast cancer case-control meta-analysis in 7/60466 cases and 1/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID PALB2_010200). This variant has been identified in 5/251482 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	University of Washington Department of Laboratory Medicine, University of Washington	Nov 20, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 08, 2022	The p.R1086* pathogenic mutation (also known as c.3256C>T), located in coding exon 12 of the PALB2 gene, results from a C to T substitution at nucleotide position 3256. This changes the amino acid from an arginine to a stop codon within coding exon 12. This mutation has been reported in multiple unrelated families with breast, ovarian and pancreatic cancer histories (Jones S et al. Science. 2009 Apr;324:217; Grant RC et al. Hum. Genomics. 2013 Apr;7:11; Zhen DB et al. Genet. Med. 2015 Jul;17:569-77; Norquist BM et al. JAMA Oncol. 2016 Apr;2:482-90; Susswein LR et al. Genet. Med. 2016 Aug;18:823-32; Sun J et al. Clin. Cancer Res. 2017 Oct;23:6113-6119). Another large case-control study identified this alteration in 1/1996 breast cancer cases and 1/1998 non-cancer controls, with the one case having bilateral breast cancer at 44 years of age (Thompson ER et al. Breast Cancer Res. 2015 Aug;17:111; Li JY et al. Int. J. Cancer. 2019 Jan;144(2):281-289). 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. -

Pancreatic cancer, susceptibility to, 3 Pathogenic:1 Other:1

risk factor, no assertion criteria provided	literature only	OMIM	Apr 10, 2009	- -
Pathogenic, no assertion criteria provided	curation	Leiden Open Variation Database	May 13, 2019	Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Marc Tischkowitz. -

PALB2-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 25, 2018

The PALB2 c.3256C>T (p.Arg1086Ter) variant is a stop-gained variant that is predicted to result in premature termination of the protein. Across a selection of the available literature, it has been reported in a heterozygous state in at least eleven individuals with cancer, including five with pancreatic cancer, three with breast cancer (one bilateral), and one with ovarian cancer (Jones et al. 2009; Grant et al. 2013; Thompson et al. 2015; Zhen et al. 2015; Norquist et al. 2016; Susswein et al. 2016; Sun et al. 2017). Five of these individuals had a family history of cancer. Although the p.Arg1086Ter variant has not been reported in the literature in individuals with Fanconi anemia, it cannot be ruled out of causing this condition based on allele frequency in consideration of condition penetrance and prevalence estimates. Control data are unavailable for this variant, which is reported at a frequency of 0.000036 in the European (non-Finnish) population of the Genome Aggregation Database. Based on the available evidence, the p.Arg1086Ter variant is classified as pathogenic for PALB2-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

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

Mar 27, 2022

- -

Breast and/or ovarian cancer Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Dec 12, 2022

- -

Breast-ovarian cancer, familial, susceptibility to, 5 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

This sequence change creates a premature translational stop signal (p.Arg1086*) in the PALB2 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in gnomAD (no frequency). This variant has been reported in individual(s) affected with pancreatic cancer (PMID: 19264984, 23561644, 25356972), breast cancer (PMID: 26283626, 26845104), and ovarian cancer (PMID: 26315354). ClinVar classifies this variant as Pathogenic, rated 2 stars, with 10 submissions, 10 publications (19264984, 23561644, 25356972, 26283626, 26315354 and 5 more) and no conflicts. Loss-of-function variants in PALB2 are known to be pathogenic (PMID: 17200668, 24136930, 25099575). Therefore, this variant has been classified as pathogenic. -

Gastric cancer Pathogenic:1

Pathogenic, no assertion criteria provided

research

Laboratory for Genotyping Development, RIKEN

Jul 01, 2021

- -

Malignant tumor of breast Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Oct 06, 2022

Variant summary: PALB2 c.3256C>T (p.Arg1086X) 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 2e-05 in 251482 control chromosomes (gnomAD). c.3256C>T has been reported in the literature in multiple individuals affected with various cancers, including breast/ovarian/pancreas/prostate/colon (e.g. Jones_2009, Grant_2013, Zhen_2015, Decker_2017, Yang_2020, Dorling_2021). The variant was reported in several affected individuals in a family (Grant_2013). Overall, these data indicate that the variant is very likely to be associated with disease. Funcational studies using a cell culture based homologous recombination assay demonstrated that the variant had complete loss of function, with similar activity seen in the empty vector control (Zhang_2021). Eleven ClinVar submitters have assessed the variant since 2014: two classified the variant as likely pathogenic, and nine as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Hereditary breast ovarian cancer syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Cancer Genomics Group, Japanese Foundation For Cancer Research

May 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.30
Cadd	Pathogenic	35
Dann	Uncertain	0.99
Eigen	Uncertain	0.27
Eigen_PC	Benign	0.031
FATHMM_MKL	Benign	0.19	N
MutationTaster	Benign	1.0	A
Vest4		0.87
GERP RS		4.1

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: rs587776527; hg19: chr16-23619279;