Submissions for variant NM_024675.4(PALB2):c.172_175del (p.Gln60fs)

dbSNP: rs180177143

Total submissions: 36

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212770	SCV000149982	pathogenic	not provided	2019-09-17	criteria provided, single submitter	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)
Ambry Genetics	RCV000116073	SCV000172718	pathogenic	Hereditary cancer-predisposing syndrome	2022-09-22	criteria provided, single submitter	clinical testing	The c.172_175delTTGT (p.Q60Rfs*7) alteration, located in exon 3 (coding exon 3) of the PALB2 gene, consists of a deletion of 4 nucleotides from position 172 to 175, causing a translational frameshift with a predicted alternate stop codon after 7 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This alteration has been reported in pancreatic, breast, and ovarian cancer patients, including multiple individuals with family histories significant for PALB2-related cancers (Jones, 2009; Casadei, 2011; Prokofyeva, 2012; Janatova, 2013; Cybulski, 2015; Kluska, 2017; Myszka, 2018). It was also seen in a patient with medulloblastoma (Waszak, 2018). Based on the available evidence, this alteration is classified as pathogenic.
Cancer Genetics Laboratory, Peter MacCallum Cancer Centre	RCV000114496	SCV000267958	likely pathogenic	Familial cancer of breast	2015-06-01	criteria provided, single submitter	case-control
Labcorp Genetics (formerly Invitae), Labcorp	RCV000114496	SCV000290814	pathogenic	Familial cancer of breast	2025-01-26	criteria provided, single submitter	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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212770	SCV000601740	pathogenic	not provided	2021-08-09	criteria provided, single submitter	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.
Color Diagnostics, LLC DBA Color Health	RCV000116073	SCV000685897	pathogenic	Hereditary cancer-predisposing syndrome	2022-12-21	criteria provided, single submitter	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.
Eurofins Ntd Llc (ga)	RCV000212770	SCV000704184	pathogenic	not provided	2016-12-09	criteria provided, single submitter	clinical testing
Counsyl	RCV000114496	SCV000785469	pathogenic	Familial cancer of breast	2017-08-15	criteria provided, single submitter	clinical testing
GeneKor MSA	RCV000116073	SCV000821755	pathogenic	Hereditary cancer-predisposing syndrome	2020-01-01	criteria provided, single submitter	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).
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000114496	SCV000840029	pathogenic	Familial cancer of breast	2018-04-27	criteria provided, single submitter	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.
CeGaT Center for Human Genetics Tuebingen	RCV000212770	SCV001247812	pathogenic	not provided	2024-02-01	criteria provided, single submitter	clinical testing	PALB2: PVS1, PS4, PS3:Supporting
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193414	SCV001362215	pathogenic	Hereditary breast ovarian cancer syndrome	2019-01-02	criteria provided, single submitter	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.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000212770	SCV001446510	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000212770	SCV001449955	pathogenic	not provided	2019-04-26	criteria provided, single submitter	clinical testing
Department of Molecular Diagnostics, Institute of Oncology Ljubljana	RCV000114496	SCV001499699	pathogenic	Familial cancer of breast	2020-04-02	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000212770	SCV002010978	pathogenic	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV001781441	SCV002016517	pathogenic	Fanconi anemia complementation group N	2019-06-13	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000114496	SCV002505617	pathogenic	Familial cancer of breast	2024-03-20	criteria provided, single submitter	clinical testing	Criteria applied: PVS1,PS4,PM5_SUP
Sema4, Sema4	RCV000116073	SCV002530642	pathogenic	Hereditary cancer-predisposing syndrome	2021-04-30	criteria provided, single submitter	curation
MGZ Medical Genetics Center	RCV000114496	SCV002580281	pathogenic	Familial cancer of breast	2022-06-03	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000114496	SCV002762828	pathogenic	Familial cancer of breast	2022-12-09	criteria provided, single submitter	research	PVS1, PS4_STR
Fulgent Genetics, Fulgent Genetics	RCV002490763	SCV002811651	pathogenic	Familial cancer of breast; Fanconi anemia complementation group N; Pancreatic cancer, susceptibility to, 3	2022-01-11	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000114496	SCV004019725	pathogenic	Familial cancer of breast	2023-04-03	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Baylor Genetics	RCV000114496	SCV004202018	pathogenic	Familial cancer of breast	2024-03-10	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000114497	SCV004242403	pathogenic	Pancreatic cancer, susceptibility to, 3	2023-12-14	criteria provided, single submitter	clinical testing	Criteria applied: PVS1,PS4
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000212770	SCV005199037	pathogenic	not provided	2023-06-28	criteria provided, single submitter	clinical testing
Department of Human Genetics, Hannover Medical School	RCV004764849	SCV005374613	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 5	2024-10-15	criteria provided, single submitter	clinical testing	ACMG/ClinGen VCEP PALB2: PVS1, PS4, PM5_Supporting
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV000116073	SCV005689695	pathogenic	Hereditary cancer-predisposing syndrome	2025-02-04	criteria provided, single submitter	clinical testing
OMIM	RCV000114497	SCV000021461	risk factor	Pancreatic cancer, susceptibility to, 3	2009-04-10	no assertion criteria provided	literature only
Leiden Open Variation Database	RCV000212770	SCV001192937	pathogenic	not provided	2020-02-28	no assertion criteria provided	curation	Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitters to LOVD: Alfons Meindl, Marc Tischkowitz.
CZECANCA consortium	RCV001270993	SCV001451805	pathogenic	Breast and/or ovarian cancer	2019-06-11	no assertion criteria provided	clinical testing
Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, Shanghai Jiao Tong University School of Medicine.	RCV001543616	SCV001754809	likely pathogenic	Colorectal cancer	2021-07-19	no assertion criteria provided	research	The Leu58fs variant in PALB2 has been reported in 1 Chinese family with autosomal dominant predisposition in familial colorectal cancer (CRC).
Clinical Genetics Laboratory, University Hospital Schleswig-Holstein	RCV000114497	SCV002029194	pathogenic	Pancreatic cancer, susceptibility to, 3	2021-10-18	no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV001193414	SCV002588982	pathogenic	Hereditary breast ovarian cancer syndrome	2022-08-26	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004739373	SCV005364629	pathogenic	PALB2-related disorder	2024-05-24	no assertion criteria provided	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.
OMIM	RCV004764849	SCV005687539	risk factor	Breast-ovarian cancer, familial, susceptibility to, 5	2009-04-10	no assertion criteria provided	literature only