rs180177143

Variant names:

• chr16-23637885-GACAA-G
• rs180177143
• NM_024675.4:c.172_175delTTGT

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_024675.4(PALB2):​c.172_175delTTGT​(p.Gln60ArgfsTer7) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000217 in 1,613,858 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. L58L) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: PALB2 NM_024675.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:36 O:2
• Conservation: PhyloP100: 1.56
• Publications: 63 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 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 16-23637885-GACAA-G is Pathogenic according to our data. Variant chr16-23637885-GACAA-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 126623.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.172_175delTTGT	p.Gln60ArgfsTer7	frameshift_variant	Exon 3 of 13	ENST00000261584.9	NP_078951.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PALB2	ENST00000261584.9	c.172_175delTTGT	p.Gln60ArgfsTer7	frameshift_variant	Exon 3 of 13	1	NM_024675.4	ENSP00000261584.4

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152126 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

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: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000398 AC: 10 AN: 251472 AF XY: 0.0000368

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000791

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000212 AC: 31 AN: 1461732 Hom.: 0 AF XY: 0.0000193 AC XY: 14 AN XY: 727188

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000765 AC: 2 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000252 AC: 28 AN: 1111894

Other (OTH) AF: 0.0000166 AC: 1 AN: 60392

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152126 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74326

African (AFR) AF: 0.0000724 AC: 3 AN: 41416

American (AMR) AF: 0.00 AC: 0 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5206

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000130 Hom.: 0

Bravo AF: 0.0000227

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:36 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:10

Dec 09, 2016

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 28, 2025

Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been identified by standard clinical testing. Female patient with breast cancer Selected ACMG criteria: Pathogenic (I):PP5;PM2;PVS1 -

Aug 09, 2021

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This frameshift variant causes the premature termination of PALB2 protein synthesis. In the published literature, this variant has been reported in individuals with breast and/or ovarian cancer, pancreatic cancer, prostate cancer, and medulloblastoma (PMID: 32339256 (2020), 31948886 (2020), 29753700 (2018), 29052111 (2018), 25452441 (2015), 24549055 (2014), and 19264984 (2009)). In addition, it has been reported in an individual with Fanconi Anemia, compound heterozygous with a PALB2 splice variant (PMID: 32052252 (2020)). Based on the available information, this variant is classified as pathogenic. -

Sep 17, 2019

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Recurrent variant in Polish and Czech populations (Janatova 2013, Cybulski 2015); Frameshift 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; Case control studies suggest this variant is associated with breast and pancreatic cancer (Cybulski 2015, Lener 2016); Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Jones 2009, Casadei 2011, Hellebrand 2011, Janatova 2013, Thompson 2015, Kluska 2017, Kraus 2017); This variant is associated with the following publications: (PMID: 26283626, 22310028, 24136930, 30716324, 19264984, 21285249, 25330149, 25959805, 21618343, 27038244, 23935381, 24982446, 28008555, 27488870, 26843898, 27099641, 27616075, 23242139, 26681312, 27757719, 28279176, 28281021, 28454591, 28724667, 28657667, 25452441, 24549055, 29052111, 29753700, 30086788, 30426508, 30322717, 31159747, 30113427, 31312277, 31757951, 29625052, 26689913, 32052252, 31447099, 31948886, 32339256) -

Feb 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PALB2: PVS1, PS4, PS3:Supporting -

Apr 26, 2019

Clinical Genetics and Genomics, Karolinska University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 28, 2023

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 28, 2020

Leiden Open Variation Database

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: curation

Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitters to LOVD: Alfons Meindl, Marc Tischkowitz. -

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial cancer of breast Pathogenic:10

Aug 15, 2017

Counsyl

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Jun 01, 2015

Cancer Genetics Laboratory, Peter MacCallum Cancer Centre

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: case-control

- -

Jan 26, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Gln60Argfs*7) 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 (rs180177143, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with pancreatic cancer (PMID: 19264984, 21285249, 21618343, 22310028, 24136930, 25959805, 27038244, 27616075). ClinVar contains an entry for this variant (Variation ID: 126623). For these reasons, this variant has been classified as Pathogenic. -

Mar 20, 2024

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Criteria applied: PVS1,PS4,PM5_SUP -

Apr 27, 2018

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A heterozygous c.172_17del (p.Gln60Argfs*7) pathogenic variant in the PALB2 gene was detected in this individual. This variant has been previously described as disease-causing in pancreatic, breast and ovarian cancer (PMID: 19264984, 27038244, 25959805, 21285249, 21285249, 22310028, 22310028). Therefore, we consider this variant to be pathogenic. -

Apr 02, 2020

Department of Molecular Diagnostics, Institute of Oncology Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 03, 2023

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. -

Dec 09, 2022

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

PVS1, PS4_STR -

Mar 10, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 03, 2022

MGZ Medical Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Pathogenic:5

Apr 30, 2021

Sema4, Sema4

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Jan 01, 2020

GeneKor MSA

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variation is a deletion of 4 nucleotides from exon 3 of the PALB2 mRNA, causing a frameshift after codon 60 and the creation of a premature translation stop signal 7 amino acid residues later p.(Gln60Argfs*7). This is expected to result in an absent or disrupted protein product. Truncating mutation in PALB2 gene are known to be pathogenic. The mutation database ClinVar contains multiple entries for this variant (Variation ID: 126623). -

Feb 04, 2025

Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1; PM5_SUP; PP1 -

Mar 26, 2025

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.172_175delTTGT pathogenic mutation, located in coding exon 3 of the PALB2 gene, results from a deletion of 4 nucleotides at nucleotide positions 172 to 175, causing a translational frameshift with a predicted alternate stop codon (p.Q60Rfs*7). This alteration has been reported in individuals diagnosed with pancreatic, breast and ovarian cancer, including multiple individuals with family histories significant for PALB2-related cancers (Jones S et al. Science. 2009 Apr;324:217; Casadei S et al. Cancer Res. 2011 Mar;71:2222-9; Prokofyeva D et al. Clin. Genet. 2012 Jul;82:100-1; Janatova M et al. Cancer Epidemiol. Biomarkers Prev. 2013 Dec;22:2323-32; Cybulski C et al. Lancet Oncol. 2015 Jun;16:638-44; Kluska A et al. BMC Med Genomics. 2017 Mar;10(1):14; Myszka A et al. Fam. Cancer. 2018 07;17(3):345-349). It was also seen in an individual diagnosed with medulloblastoma (Waszak SM et al. Lancet Oncol. 2018 06;19(6):785-798). 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. -

Jun 03, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant deletes 4 nucleotides in exon 3 of the PALB2 gene, creating a frameshift and 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 over 15 individuals affected with breast and/or ovarian cancer (PMID: 21285249, 21618343, 22310028, 24136930, 25099575, 25452441, 26283626, 27616075, 28724667, 29052111), 2 individuals affected with pancreatic cancer (PMID: 19264984, 27038244) and an individual affected with medulloblastoma (PMID: 29753700). This variant also has been reported in a breast cancer case-control study in 40/12529 cases and 10/4702 unaffected individuals (OR = 4.02, 95% CI 1.6 to 16.2) and a breast cancer case-control meta-analysis in 24/60466 cases and 9/53461 unaffected individuals (OR = 2.358, 95%CI 1.096 to 5.074) (PMID: 25959805, 33471991; Leiden Open Variation Database DB-ID PALB2_010002). This variant has been identified in 12/282872 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. -

Pancreatic cancer, susceptibility to, 3 Pathogenic:2 Other:1

Apr 10, 2009

OMIM

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Dec 14, 2023

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Criteria applied: PVS1,PS4 -

Oct 18, 2021

Clinical Genetics Laboratory, University Hospital Schleswig-Holstein

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Hereditary breast ovarian cancer syndrome Pathogenic:2

Aug 26, 2022

BRCAlab, Lund University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 02, 2019

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: PALB2 c.172_175delTTGT (p.Gln60ArgfsX7) 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. The variant allele was found at a frequency of 4e-05 in 277228 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in PALB2 causing Hereditary Breast and Ovarian Cancer (4e-05 vs 0.00016), allowing no conclusion about variant significance. c.172_175delTTGT has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (Hellebrand 2011, Casadei 2011 ,Kraus 2016) and pancreatic cancer (Jones 2009). These data indicate that the variant is very likely to be associated with disease. In addition, a case-control study found this variant to be present at a significantly higher frequency in breast cancer patients than in unaffected controls (OR=5.02; p=0.0016) (Cybulski 2015). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Ten 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 (9)/likely pathogenic(1). Based on the evidence outlined above, the variant was classified as pathogenic. -

Breast-ovarian cancer, familial, susceptibility to, 5 Pathogenic:1 Other:1

Apr 10, 2009

OMIM

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Oct 15, 2024

Department of Human Genetics, Hannover Medical School

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG/ClinGen VCEP PALB2: PVS1, PS4, PM5_Supporting -

Familial cancer of breast;C1835817:Fanconi anemia complementation group N;C3150547:Pancreatic cancer, susceptibility to, 3 Pathogenic:1

Jan 11, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

PALB2-related disorder Pathogenic:1

May 24, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PALB2 c.172_175delTTGT variant is predicted to result in a frameshift and premature protein termination (p.Gln60Argfs*7). This variant has been frequently reported as pathogenic in individuals with a history of breast, pancreatic, and ovarian cancers (Jones et al. 2009. PubMed ID: 19264984; Lener et al. 2016. PubMed ID: 27038244; Casadei et al. 2011. PubMed ID: 21285249; Hellebrand et al. 2011. PubMed ID: 21618343; Kraus et al. 2017. PubMed ID: 27616075; Prokofyeva et al. 2012. PubMed ID: 22310028). Of note, this variant is also reported to be a founder variant in individuals of Czech and Polish ancestry (Lener et al. 2016. PubMed ID: 27038244). This variant is reported in 0.0096% of alleles in individuals of Ashkenazi Jewish descent in gnomAD and is interpreted as Pathogenic/Likely pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/126623/). Frameshift variants in PALB2 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Fanconi anemia complementation group N Pathogenic:1

Jun 13, 2019

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breast and/or ovarian cancer Pathogenic:1

Jun 11, 2019

CZECANCA consortium

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Colorectal cancer Pathogenic:1

Jul 19, 2021

Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, Shanghai Jiao Tong University School of Medicine.

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

The Leu58fs variant in PALB2 has been reported in 1 Chinese family with autosomal dominant predisposition in familial colorectal cancer (CRC). -

Fanconi anemia complementation group N;C3150547:Pancreatic cancer, susceptibility to, 3;C5830615:Breast-ovarian cancer, familial, susceptibility to, 5 Pathogenic:1

Dec 12, 2019

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.6
Mutation Taster		=0/200	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: rs180177143; hg19: chr16-23649206; COSMIC: COSV55170212;