rs587782005

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_024675.4(PALB2):c.424A>T(p.Lys142Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000744 in 1,613,488 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. K142K) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

PALB2
NM_024675.4 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:13

Conservation

PhyloP100: 0.256

Variant links:

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]

PALB2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 16-23636122-T-A is Pathogenic according to our data. Variant chr16-23636122-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 141779.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PALB2	NM_024675.4 linkuse as main transcript	c.424A>T	p.Lys142Ter	stop_gained	4/13	ENST00000261584.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PALB2	ENST00000261584.9 linkuse as main transcript	c.424A>T	p.Lys142Ter	stop_gained	4/13	1	NM_024675.4	P1

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151850

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

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:

0.00000796

AC:

AN:

251270

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135790

show subpopulations

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:

0.00000684

AC:

AN:

1461638

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727108

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

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:

0.00000809

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000132

AC:

AN:

151850

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74166

show subpopulations

Gnomad4 AFR

AF:

0.0000242

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

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial cancer of breast

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Feb 06, 2018	- -
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	Baylor Genetics	Mar 13, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 13, 2024	This sequence change creates a premature translational stop signal (p.Lys142*) 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 (rs587782005, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 28779002). ClinVar contains an entry for this variant (Variation ID: 141779). For these reasons, this variant has been classified as Pathogenic. -

Hereditary cancer-predisposing syndrome

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 22, 2022	The p.K142* pathogenic mutation (also known as c.424A>T), located in coding exon 4 of the PALB2 gene, results from an A to T substitution at nucleotide position 424. This changes the amino acid from a lysine to a stop codon within coding exon 4. This mutation was identified in a cohort of breast cancer patients from the UK and was not present in controls (Decker B et al. J. Med. Genet. 2017 Nov;54:732-741). 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	Jul 16, 2017	- -
Pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Mar 09, 2022	- -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 22, 2023	Nonsense variant predicted to result in protein truncation and 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); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 28152038, 28779002, 29922827, 26689913, 29625052, 17200672, 17200671, 17200668, 25099575, 35753512, 33471991, 30322717, 24136930, 32885271) -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 24, 2022	The PALB2 c.424A>T; p.Lys142Ter variant (rs587782005) is reported in the literature in individuals affected with breast or ovarian cancer (Carter 2018, Decker 2017, Huang 2018). This variant is also reported in ClinVar (Variation ID: 141779), but is only observed on two alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Carter NJ et al. Germline pathogenic variants identified in women with ovarian tumors. Gynecol Oncol. 2018 Dec;151(3):481-488. PMID: 30322717. Decker B et al. Rare, protein-truncating variants in ATM, CHEK2 and PALB2, but not XRCC2, are associated with increased breast cancer risks. J Med Genet. 2017 Nov;54(11):732-741. PMID: 28779002. Huang KL et al. Pathogenic Germline Variants in 10,389 Adult Cancers. Cell. 2018 Apr 5;173(2):355-370.e14. PMID: 29625052. -

Malignant tumor of breast

Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The PALB2 p.Lys142X variant was not identified in the literature nor was it identified in the COSMIC, MutDB, LOVD 3.0, or Zhejiang Colon Cancer databases. The variant was identified in dbSNP (ID: rs587782005) as â€šÃ„ÃºWith Pathogenic alleleâ€šÃ„Ã¹, and in the ClinVar and Clinvitae databases (3x classified as pathogenic by Ambry Genetics, GeneDx and Invitae). The variant was identified in control databases in 2 of 246078 chromosomes at a frequency of 0.000008 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include European (Non-Finnish) in 2 of 111646 chromosomes (freq: 0.000018), while the variant was not observed in the African, Ashkenazi Jewish, East Asian, European (Finnish), Latino, Other, and South Asian populations. The c.424A>T variant leads to a premature stop codon at position 142 which is predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the PALB2 gene are an established mechanism of disease in breast cancer and is the type of variant expected to cause the disorder. In summary, based on the above information this variant meets our laboratoryâ€šÃ„Ã´s criteria to be classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 17, 2021	Variant summary: PALB2 c.424A>T (p.Lys142X) 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 251270 control chromosomes (gnomAD). c.424A>T has been reported in the literature in individuals affected with breast cancer and ovarian cancer (e.g. Decker_2017, Carter_2018, Huang_2018). These data indicate that the variant is likely to be associated with disease. Five ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

PALB2-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Sep 11, 2023

PVS1, PS4, PM2 -

Breast cancer, susceptibility to

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

National Institute of Allergy and Infectious Diseases - Centralized Sequencing Program, National Institutes of Health

Aug 06, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.59

BayesDel_noAF

Pathogenic

0.53

Cadd

Pathogenic

Dann

Uncertain

0.99

Eigen

Uncertain

0.24

Eigen_PC

Benign

-0.0044

FATHMM_MKL

Benign

0.34

MutationTaster

Benign

1.0

Vest4

0.81

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over