rs180177110

chr16-23629897-G-Achr16-23629897-G-Cchr16-23629897-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.2257C>T(p.Arg753Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000991 in 1,614,054 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 Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R753R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: PALB2 NM_024675.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:22
• Conservation: PhyloP100: 0.369

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 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 16-23629897-G-A is Pathogenic according to our data. Variant chr16-23629897-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 142403.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23629897-G-A is described in Lovd as [Pathogenic]. Variant chr16-23629897-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PALB2	NM_024675.4	c.2257C>T	p.Arg753Ter	stop_gained	5/13	ENST00000261584.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PALB2	ENST00000261584.9	c.2257C>T	p.Arg753Ter	stop_gained	5/13	1	NM_024675.4	P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152164 Hom.: 0 Cov.: 32

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: 0.0000239 AC: 6 AN: 251486 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135918

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: 0.0000440

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1461890 Hom.: 0 Cov.: 32 AF XY: 0.0000110 AC XY: 8 AN XY: 727244

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.0000117

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152164 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74322

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: 0.0000151

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:22

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 16, 2022	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; This variant is associated with the following publications: (PMID: 28486781, 28779002, 31446535, 29922827, 28888541, 31721094, 21618343, 21182766, 19264984, 19763884, 25186627, 25452441, 25099575, 20346647, 20852946, 21165770, 27276934, 27783279, 28281021, 27798748, 27553368, 25525159, 28423363, 29338689, 29093764, 28724667, 28152038, 29752822, 28135719, 29915322, 29566657, 30306255, 30613976, 30303537, 31786208, 31300551, 29625052, 31447099, 32854451, 32832836, 32339256, 34026625, 34399810, 31589614, 32885271, 30982232, 33128190, 31785789, 33169439, 17200671, 31089269) -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 20, 2021	This nonsense variant causes the premature termination of PALB2 protein synthesis. In addition, it has been reported in individuals affected with prostate cancer and breast cancer in the published literature (PMID: 32854451 (2020), 32832836 (2020), 32339256 (2020), 31786208 (2020), 31300551 (2020), 31089269 (2019), 30982232 (2019), 30287823 (2018), 29752822 (2018), 29566657 (2018)). This variant has also been reported to have a deleterious effect on PALB2 homologous recombination activity (PMID: 33169439 (2021)). Based on the available information, this variant is classified as a pathogenic. -
Pathogenic, no assertion criteria provided	curation	Leiden Open Variation Database	Dec 23, 2019	Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitters to LOVD: Alfons Meindl, Arleen D. Auerbach, Florentia Fostira, LOVD-team, but with Curator vacancy, Marc Tischkowitz, Yukihide Momozawa. -
Pathogenic, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The PALB2 p.Arg753X variant was identified in 4 of 2534 proband chromosomes (frequency: 0.002) from German, Korean and Italian individuals or families with BRCA1/2 negative breast cancers and multiethnic individuals with Fanconi anemia, and was not identified in 1500 chromosomes from healthy individuals (Reid 2007, Hellebrand 2011, Kim 2017, Papi 2010). The variant was seen in biallelism with PALB2 3549C>A/Y1183X in 1 Fanconi anemia proband, with both parents carrying each of the alleles (Reid 2007). The variant was also identified in dbSNP (ID: rs180177110) “With Pathogenic allele”, ClinVar (classified as pathogenic by Ambry Genetics, GeneDx and Invitae), Clinvitae (3x), Cosmic (1x in a breast carcinoma), Zhejiang Colon Cancer Database (1x), and in control databases in 6 of 246268 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017), noting that the variant falls on 3 transcripts in the PALB2 gene. Breakdown of the observations by population include Other in 1 of 5486 chromosomes (freq: 0.0002), and European Non-Finnish in 5 of 111716 chromosomes (freq: 0.00005), while the variant was not observed in the African, Latino, Ashkenazi Jewish, East Asian, European Finnish, and South Asian populations. The p.Arg753X variant leads to a premature stop codon at position 753 which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the PALB2 gene are an established mechanism of disease in hereditary breast and ovarian cancer and is the type of variant expected to cause the disorder. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -

Hereditary cancer-predisposing syndrome Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 19, 2021	The p.R753* pathogenic mutation (also known as c.2257C>T), located in coding exon 5 of the PALB2 gene, results from a C to T substitution at nucleotide position 2257. This changes the amino acid from an arginine to a stop codon within coding exon 5. This mutation was reported in conjunction with a second nonsense mutation in a child with Fanconi anemia type N (FA-N) (Reid S et al. Nat. Genet. 2007 Feb;39(2):162-4). This mutation has also been detected in multiple patients and families with hereditary breast and/or ovarian cancer (Papi L et al. Fam. Cancer. 2010 Jun;9(2):181-5; Hellebrand H et al. Hum. Mutat. 2011 Jun;32(6):E2176-88; Antoniou AC et al. N. Engl. J. Med. 2014 Aug;371(6):497-506; Couch FJ et al. J. Clin. Oncol. 2015 Feb;33(4):304-11; Tung N et al. Cancer, 2015 Jan;121:25-33; Decker B et al. J. Med. Genet., 2017 Nov;54:732-741; Kim H et al. Breast Cancer Res. Treat. 2017 Jan;161:95-102; Lolas Hamameh S et al. Int. J. Cancer, 2017 08;141:750-756; Moran O et al. Breast Cancer Res. Treat. 2017 Jan;161:135-142; Sun J et al. Clin. Cancer Res., 2017 Oct;23:6113-6119; Tedaldi G et al. Oncotarget, 2017 Jul;8:47064-47075; Li JY et al. Int. J. Cancer, 2018 May; Momozawa Y et al. Nat Commun, 2018 Oct;9:4083; Park JS et al. BMC Cancer, 2018 01;18:83; Wang YA et al. BMC Cancer, 2018 03;18:315; Bonache S et al. J Cancer Res Clin Oncol, 2018 Dec;144:2495-2513; Wang J et al. Cancer Med, 2019 05;8:2074-2084; Vagena A et al. J Hum Genet, 2019 Aug;64:767-773; Fostira F et al. J Med Genet, 2020 01;57:53-61; Girard E et al. Int J Cancer, 2019 04;144:1962-1974; Fanale D et al. Cancers (Basel), 2020 Aug;12; Zhou J et al. Cancer, 2020 07;126:3202-3208; Rodríguez-Balada M et al. Clin Biochem, 2020 Feb;76:17-23; Jian W et al. Hered Cancer Clin Pract, 2017 Oct;15:19; Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879), as well as at least one prostate cancer patient (Matejcic M et al. JCO Precis Oncol, 2020 Jan;4:32-43). In addition to the evidence 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	Mendelics	Jul 02, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneKor MSA	Jan 01, 2020	This is a nonsense variant creating a premature translational stop signal at codon 753 (p.Arg753*) in the PALB2 gene. It is expected to result in an absent or disrupted protein product. This particular variant has been reported in the literature in individuals affected with breast cancer (PMID: 25452441) and Fanconi anemia (PMID: 17200671) . The mutation database ClinVar contains entries for this variant (Variation ID: 142403). -
Pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Mar 31, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 24, 2023	This variant changes 1 nucleotide in exon 5 of the PALB2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. A functional study has reported for this variant resulted in the loss of homology-mediated repair activity (PMID: 33169439). This variant has been reported in individuals affected with breast cancer (PMID: 19763884, 21618343, 25099575, 25186627, 25452441, 27783279, 27798748, 28423363, 28486781, 28724667, 28779002, 29093764, 29338689, 30287823, 29752822, 31089269, 31300551, 31786208, 32339256, 32854451, 32885271, 33471991, 36605468; doi: 10.21037/tbcr-22-33; Leiden Open Variation Database DB-ID PALB2_000007). This variant has been observed in compound heterozygous state with another pathogenic variant in an individual affected with Fanconi anemia (PMID: 17200671). This variant has been identified in 6/251486 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. -

Familial cancer of breast Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Jun 03, 2017	This c.2257C>T (p.Arg753*) variant in the PALB2 gene has been detected in a cohort of 818 breast cancer patients [PMID 21618343]. The proband was diagnosed with breast cancer at 33 years old. The variant was inherited from the mother who also had breast cancer at 66 years old. The maternal grandmother also had breast cancer at 43 years old but the PALB2 status was unavailable. The variant was also detected in a cohort of 235 Korean patients with hereditary breast cancer [PMID 27783279]. This c.2257C>T (p.Arg753*) variant has also been reported in a compound heterozygous patient with Fanconi Anemia N [PMID 17200671]. This c.2257C>T (p.Arg753*) change has been observed in 6 heterozygous individual in GnomAD (http://gnomad.broadinstitute.org/variant/16-23641217-C-T). The c.2257C>T change creates a stop codon at amino acid position 753 of the PALB2 protein and is thus predicted to lead to a loss of function of the PALB2 protein. This c.2257C>T (p.Arg753*) variant is thus classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jul 12, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 10, 2024	This sequence change creates a premature translational stop signal (p.Arg753*) 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 (rs180177110, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 17200671, 19763884, 20852946, 21618343, 25186627, 25452441). ClinVar contains an entry for this variant (Variation ID: 142403). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 31, 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	Counsyl	Apr 25, 2017	- -

Hereditary breast ovarian cancer syndrome Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Aug 26, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 01, 2022	The p.Arg753X variant in PALB2 has been reported in > 20 individuals breast cancer or other PALB2-related cancers and segregated with disease in 6 affected individuals from at least 3 families (Jones 2009 PMID: 19264984, Papi 2010 PMID: 19763884, Hellebrand 2011 PMID: 21618343, Kim 2016 PMID: 27783279, Vagena 2019 PMID: 31089269, Fostira 2020 PMID: 31300551, Zhou 2020 PMID: 32339256). Haplotype testing suggests that this is a founder variant in the Greek population (Vagena 2019 PMID: 31089269). In addition, this variant has been reported in one individual with Fanconi Anemia, who also carried a second PALB2 pathogenic variant on the other allele, further supporting pathogenicity (Reid 2007 PMID: 17200671). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 142403) and has also been identified in 0.004395% (5/113762) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This nonsense variant leads to a premature termination codon at position 753, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the PALB2 gene is an established disease mechanism in autosomal dominant inherited predisposition to PALB2-associated cancers, including breast cancer. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant inherited predisposition to PALB2-associated cancers. ACMG/AMP Criteria applied: PVS1, PS4, PP1_Moderate, PM2_Supporting. -

Breast and/or ovarian cancer Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Mar 03, 2023

- -

Fanconi anemia complementation group N Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Jan 04, 2019

- -

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 09, 2020

Variant summary: PALB2 c.2257C>T (p.Arg753X) 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 2.4e-05 in 251486 control chromosomes. c.2257C>T has been reported in the literature in multiple individuals affected with Fanconi Anemia (e.g. Reid_2007) and Breast Cancer (e.g. Hellebrand_2011, Tung_2015, Jian_2017, Sun_2017, Rodriguez-Balda_2020). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. 12 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. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.28
Cadd	Pathogenic	31
Dann	Uncertain	0.99
Eigen	Uncertain	0.20
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.10	N
MutationTaster	Benign	1.0	A
Vest4		0.70
GERP RS		2.9

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: rs180177110; hg19: chr16-23641218; COSMIC: COSV55163432;