ClinVar Miner

Submissions for variant NM_024675.4(PALB2):c.172_175del (p.Gln60fs) (rs180177143)

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Total submissions: 19
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212770 SCV000149982 pathogenic not provided 2018-10-18 criteria provided, single submitter clinical testing This pathogenic variant is denoted PALB2 c.172_175delTTGT at the cDNA level and p.Gln60ArgfsX7 (Q60RfsX7) at the protein level. The normal sequence, with the bases that are deleted in brackets, is TTGT[delTTGT]CTCA. The deletion causes a frameshift, changing a Glutamine to an Arginine at codon 60, and creates a premature stop codon at position 7 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been described as a recurrent variant in Polish and Czech populations and has been reported in several individuals with personal and/or family history of breast or pancreatic cancer (Jones 2009, Casadei 2011, Hellebrand 2011, Janatova 2013, Thompson 2015, Kraus 2016, Lener 2016, Pritzlaff 2016, Kluska 2017), with one case-control study finding this variant to be present at a significantly higher frequency in women with breast cancer as compared to unaffected controls (OR=5.02; p=0.0016) (Cybulski 2015). We consider PALB2 c.172_175delTTGT to be pathogenic.
Ambry Genetics RCV000116073 SCV000172718 pathogenic Hereditary cancer-predisposing syndrome 2019-03-22 criteria provided, single submitter 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 pancreatic, breast, and ovarian cancer patients to date, 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 a patient 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.
Cancer Genetics Laboratory,Peter MacCallum Cancer Centre RCV000114496 SCV000267958 likely pathogenic Familial cancer of breast 2015-06-01 criteria provided, single submitter case-control
Invitae RCV000114496 SCV000290814 pathogenic Familial cancer of breast 2020-10-30 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. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been observed in multiple individuals affected with pancreatic cancer (PMID: 19264984, 27038244), breast cancer (PMID: 25959805, 21285249, 22310028, 21618343, 24136930, 27616075), and ovarian cancer (PMID: 22310028). ClinVar contains an entry for this variant (Variation ID: 126623). Loss-of-function variants in PALB2 are known to be pathogenic (PMID: 17200668, 24136930, 25099575). For these reasons, this variant has been classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212770 SCV000601740 pathogenic not provided 2017-02-24 criteria provided, single submitter clinical testing
Color Health, Inc RCV000116073 SCV000685897 pathogenic Hereditary cancer-predisposing syndrome 2021-02-16 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 individuals affected with breast/ovarian cancer (PMID: 21285249, 25099575, 25452441, 25959805, 26283626, 27616075, 28724667, 29052111) or pancreatic cancer (19264984, 27038244). 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.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics 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 Praxis fuer Humangenetik Tuebingen RCV000212770 SCV001247812 pathogenic not provided 2017-04-01 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001193414 SCV001362215 pathogenic Hereditary breast and 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 Karolinska University Hospital,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
OMIM RCV000114497 SCV000021461 risk factor Pancreatic cancer 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).

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