NM_024675.4:c.2079delT

Variant names:

• chr16-23630074-TA-T
• rs878855105
• NM_024675.4:c.2079delT

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_024675.4(PALB2):​c.2079delT​(p.His693GlnfsTer16) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. H693H) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PALB2 NM_024675.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 0.346
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• hereditary breast carcinoma

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen, Ambry Genetics
• Fanconi anemia complementation group N

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
• pancreatic cancer, susceptibility to, 3

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• familial ovarian cancer

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary nonpolyposis colon cancer

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 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 16-23630074-TA-T is Pathogenic according to our data. Variant chr16-23630074-TA-T is described in CliVar as Pathogenic. Clinvar id is 241539.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23630074-TA-T is described in CliVar as Pathogenic. Clinvar id is 241539.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23630074-TA-T is described in CliVar as Pathogenic. Clinvar id is 241539.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23630074-TA-T is described in CliVar as Pathogenic. Clinvar id is 241539.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23630074-TA-T is described in CliVar as Pathogenic. Clinvar id is 241539.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23630074-TA-T is described in CliVar as Pathogenic. Clinvar id is 241539.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23630074-TA-T is described in CliVar as Pathogenic. Clinvar id is 241539.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23630074-TA-T is described in CliVar as Pathogenic. Clinvar id is 241539.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23630074-TA-T is described in CliVar as Pathogenic. Clinvar id is 241539.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23630074-TA-T is described in CliVar as Pathogenic. Clinvar id is 241539.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23630074-TA-T is described in CliVar as Pathogenic. Clinvar id is 241539.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23630074-TA-T is described in CliVar as Pathogenic. Clinvar id is 241539.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23630074-TA-T is described in CliVar as Pathogenic. Clinvar id is 241539.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23630074-TA-T is described in CliVar as Pathogenic. Clinvar id is 241539.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23630074-TA-T is described in CliVar as Pathogenic. Clinvar id is 241539.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23630074-TA-T is described in CliVar as Pathogenic. Clinvar id is 241539.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23630074-TA-T is described in CliVar as Pathogenic. Clinvar id is 241539.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23630074-TA-T is described in CliVar as Pathogenic. Clinvar id is 241539.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23630074-TA-T is described in CliVar as Pathogenic. Clinvar id is 241539.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23630074-TA-T is described in CliVar as Pathogenic. Clinvar id is 241539.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23630074-TA-T is described in CliVar as Pathogenic. Clinvar id is 241539.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23630074-TA-T is described in CliVar as Pathogenic. Clinvar id is 241539.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23630074-TA-T is described in CliVar as Pathogenic. Clinvar id is 241539.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23630074-TA-T is described in CliVar as Pathogenic. Clinvar id is 241539.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23630074-TA-T is described in CliVar as Pathogenic. Clinvar id is 241539.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23630074-TA-T is described in CliVar as Pathogenic. Clinvar id is 241539.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23630074-TA-T is described in CliVar as Pathogenic. Clinvar id is 241539.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23630074-TA-T is described in CliVar as Pathogenic. Clinvar id is 241539.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23630074-TA-T is described in CliVar as Pathogenic. Clinvar id is 241539.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23630074-TA-T is described in CliVar as Pathogenic. Clinvar id is 241539.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23630074-TA-T is described in CliVar as Pathogenic. Clinvar id is 241539.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23630074-TA-T is described in CliVar as Pathogenic. Clinvar id is 241539.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23630074-TA-T is described in CliVar as Pathogenic. Clinvar id is 241539.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PALB2	NM_024675.4	c.2079delT	p.His693GlnfsTer16	frameshift_variant	Exon 5 of 13	ENST00000261584.9	NP_078951.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PALB2	ENST00000261584.9	c.2079delT	p.His693GlnfsTer16	frameshift_variant	Exon 5 of 13	1	NM_024675.4	ENSP00000261584.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial cancer of breast Pathogenic:2

Jul 19, 2024

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -

Jun 16, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in PALB2 are known to be pathogenic (PMID: 17200668, 24136930, 25099575). This variant has not been reported in the literature in individuals with PALB2-related conditions. ClinVar contains an entry for this variant (Variation ID: 241539). This sequence change creates a premature translational stop signal (p.His693Glnfs*16) in the PALB2 gene. It is expected to result in an absent or disrupted protein product. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.35
Mutation Taster		=1/199	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs878855105; hg19: chr16-23641395;