rs587782531

chr16-23635884-AC-TA

Variant summary

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

The NM_024675.4(PALB2):c.661_662delinsTA(p.Val221Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. V221V) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PALB2 NM_024675.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: -0.571

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 16-23635884-AC-TA is Pathogenic according to our data. Variant chr16-23635884-AC-TA is described in ClinVar as [Pathogenic]. Clinvar id is 142540.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	c.661_662delinsTA	p.Val221Ter	stop_gained	4/13	ENST00000261584.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PALB2	ENST00000261584.9	c.661_662delinsTA	p.Val221Ter	stop_gained	4/13	1	NM_024675.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial cancer of breast Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	May 08, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 19, 2023	This sequence change creates a premature translational stop signal (p.Val221*) 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). Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This premature translational stop signal has been observed in individual(s) with breast cancer and male breast cancer and thyroid cancer (PMID: 24136930, 28008555). ClinVar contains an entry for this variant (Variation ID: 142540). 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	Myriad Genetics, Inc.	Sep 06, 2023	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -

Malignant tumor of breast Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 04, 2021	Variant summary: PALB2 c.661_662delinsTA (p.Val221X) 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 was absent in 251302 control chromosomes. c.661_662delinsTA has been reported in the literature in individuals affected with breast cancer (Janatova_2013) and breast/thyroid cancer (Pritzlaff_2013). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories and one database (LOVD) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The PALB2 p.Val221X variant was identified in 3 of 6406 proband chromosomes (frequency: 0.0005) from individuals or families with breast cancer and was not identified in 2452 control chromosomes from healthy individuals (Janatova 2013, LaDuca 2014, Pritzlaff 2017). The variant was also identified in the following databases: dbSNP (ID: rs587782531) as "With Pathogenic allele", ClinVar/Clinvitae (2x, pathogenic), and LOVD 3.0 (1x). The variant was not identified in Cosmic, MutDB, or Zhejiang Colon Cancer Database. The variant was not identified in the control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The c.661_662delinsTA variant leads to a premature stop codon at position 221 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 breast 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. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Sep 06, 2023

Not observed in large population cohorts (gnomAD); 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; 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: 24136930, 24763289, 28008555, 28152038, 29649263, 28888541, 37065479) -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 14, 2022

The c.661_662delGTinsTA pathogenic mutation, located in coding exon 4 of the PALB2 gene, results from an in-frame deletion of GT and insertion of TA at nucleotide positions 661 and 662. This changes the amino acid from a valine to a stop codon at codon 221 and this alteration can also be designated as p.V221*. This mutation has been reported in the literature in an individual with a personal and family history of breast cancer (Janatova M et al., Cancer Epidemiol. Biomarkers Prev. 2013 Dec; 22(12):2323-32) and in a male diagnosed with breast cancer and thyroid cancer (Pritzlaff M et al. Breast Cancer Res. Treat., 2017 02;161:575-586). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs587782531; hg19: chr16-23647205;