rs180177091

chr16-23635795-G-Achr16-23635795-G-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.751C>T(p.Gln251Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,614,024 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. Q251Q) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PALB2 NM_024675.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:13
• Conservation: PhyloP100: 0.383

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 16-23635795-G-A is Pathogenic according to our data. Variant chr16-23635795-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 126767.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23635795-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PALB2	NM_024675.4	c.751C>T	p.Gln251Ter	stop_gained	4/13	ENST00000261584.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PALB2	ENST00000261584.9	c.751C>T	p.Gln251Ter	stop_gained	4/13	1	NM_024675.4	P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152174 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: 0.000193

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

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461850 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2 AN XY: 727226

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152174 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74348

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000113

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial cancer of breast Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	May 10, 2023	- -
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	Institute of Human Genetics, University of Leipzig Medical Center	Oct 30, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	New York Genome Center	Jun 17, 2022	The c.751C>T variant identified in PALB2 has previously been reported in multiple individuals affected with breast cancer [PMID: 18446436, 26541979, 26720728, 28724667, 28825143, 33646313, 32339256]. The variant has been deposited in ClinVar [ClinVar ID: 126767] as Pathogenic by multiple submitters. The c.751C>T variant is observed in 3 alleles (0.0003% minor allele frequency with 0 homozygotes) in population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8, All of Us), suggesting it is not a common benign variant in the populations represented in those databases. The c.751C>T variant is located in exon 4 of this 13-exon gene, predicted to incorporate a premature termination codon (p.(Gln251Ter)), and is expected to result in loss-of-function via nonsense-mediated decay. Multiple loss-of-function variants downstream to the c.751C>T variant have been reported in the literature and ClinVar in individuals with familial breast cancer. Based on available evidence this inherited c.751C>T p.(Gln251Ter) variant identified in PALB2 is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Sep 06, 2023	This sequence change creates a premature translational stop signal (p.Gln251*) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 18446436, 26541979, 26720728, 28724667, 28825143). ClinVar contains an entry for this variant (Variation ID: 126767). For these reasons, this variant has been classified as Pathogenic. -
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	Counsyl	Oct 23, 2017	- -

Hereditary cancer-predisposing syndrome Pathogenic:4

Pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	May 19, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 21, 2022	The p.Q251* pathogenic mutation (also known as c.751C>T), located in coding exon 4 of the PALB2 gene, results from a C to T substitution at nucleotide position 751. This changes the amino acid from a glutamine to a stop codon within coding exon 4. This mutation has been identified in several Chinese breast cancer cohorts (Cao AY et al. Breast Cancer Res. Treat. 2009 Apr;114(3):457-62; Sun J et al. Clin. Cancer Res. 2017 Oct;23(20):6113-6119; Zhang K et al. Breast Cancer Res. Treat. 2017 Dec;166(3):865-873) and in one individual with papillary serous ovarian cancer (Norquist BM et al. JAMA Oncol 2016 Apr;2(4):482-90). 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	University of Washington Department of Laboratory Medicine, University of Washington	Nov 20, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 28, 2022	This variant changes 1 nucleotide in exon 4 of the PALB2 gene, creating a 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 eight individuals affected with breast and ovarian cancer (PMID: 18446436, 26541979, 26720728, 28724667, 28825143; Color internal data). This variant has not been identified 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. -

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 22, 2023

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Aug 30, 2018

This pathogenic variant is denoted PALB2 c.751C>T at the cDNA level and p.Gln251Ter (Q251X) at the protein level. The substitution creates a nonsense variant, which changes a Glutamine to a premature stop codon (CAG>TAG), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been reported in individuals with early-onset breast cancer or ovarian cancer (Cao 2009, Tischkowitz 2010, Hasmad 2015, Norquist 2016, Sun 2017) and is considered pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Uncertain	0.050
Cadd	Pathogenic	26
Dann	Uncertain	1.0
Eigen	Benign	0.18
Eigen_PC	Benign	-0.17
FATHMM_MKL	Benign	0.054	N
MutationTaster	Benign	1.0	A
Vest4		0.81
GERP RS		1.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs180177091; hg19: chr16-23647116; COSMIC: COSV105056746; COSMIC: COSV105056746;