ClinVar Miner

Submissions for variant NM_024675.3(PALB2):c.196C>T (p.Gln66Ter) (rs180177083)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000163078 SCV000213579 pathogenic Hereditary cancer-predisposing syndrome 2018-08-06 criteria provided, single submitter clinical testing The p.Q66* pathogenic mutation (also known as c.196C>T), located in coding exon 3 of the PALB2 gene, results from a C to T substitution at nucleotide position 196. This changes the amino acid from a glutamine to a stop codon within coding exon 3. This mutation has been identified in multiple families of various ethnicities with breast cancer (Casadei S et al. Cancer Res. 2011 Mar;71:2222-9; Wong MW et al. Breast Cancer Res. Treat. 2011 Jun;127:853-9; Teo ZL et al. Breast Cancer Res. 2013 Feb;15:R17; Antoniou AC et al. N. Engl. J. Med. 2014 Aug;371:497-506; Thompson ER et al. Breast Cancer Res. 2015 Aug;17:111). 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.
Invitae RCV000114503 SCV000253937 pathogenic Familial cancer of breast 2020-10-18 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gln66*) in the PALB2 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the literature in families affected with breast and ovarian cancer (PMID: 21285249, 21409391, 23448497, 26534844). ClinVar contains an entry for this variant (Variation ID: 126629). 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.
Cancer Genetics Laboratory,Peter MacCallum Cancer Centre RCV000114503 SCV000267959 likely pathogenic Familial cancer of breast 2015-06-01 criteria provided, single submitter case-control
GeneDx RCV000235795 SCV000292642 pathogenic not provided 2019-04-23 criteria provided, single submitter clinical testing 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; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 21409391, 25447460, 17420451, 27878467, 22692731, 25099575, 25863477, 26283626, 25525159, 23935381, 24206657, 27485037, 23448497, 26534844, 24870022, 28779002, 26786923, 21285249)
Counsyl RCV000114503 SCV000487889 likely pathogenic Familial cancer of breast 2015-12-07 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000235795 SCV000601747 pathogenic not provided 2017-01-31 criteria provided, single submitter clinical testing
Color Health, Inc RCV000163078 SCV000685912 pathogenic Hereditary cancer-predisposing syndrome 2021-02-11 criteria provided, single submitter clinical testing This variant changes 1 nucleotide in exon 3 of the PALB2 gene, creating a 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 cancer (PMID: 21285249, 21409391, 23448497, 23787919, 24206657, 25099575, 26534844, 26786923, 27878467). This variant has been identified in 2/251474 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000588616 SCV000699549 pathogenic Hereditary breast and ovarian cancer syndrome 2021-03-04 criteria provided, single submitter clinical testing Variant summary: PALB2 c.196C>T (p.Gln66X) 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 allele was found at a frequency of 8e-06 in 251474 control chromosomes. c.196C>T has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (e.g. Casadei_2011, Wong_2011, Nguyen-Dumont_2013, Thompson_2015). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. 12 other ClinVar submitters (evaluation after 2014) have cited the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center RCV000114503 SCV001440261 pathogenic Familial cancer of breast 2019-01-01 criteria provided, single submitter clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000235795 SCV001447920 pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
Knight Diagnostic Laboratories, Oregon Health and Sciences University RCV000163078 SCV001448736 pathogenic Hereditary cancer-predisposing syndrome 2019-04-24 criteria provided, single submitter clinical testing
True Health Diagnostics RCV000163078 SCV000805276 pathogenic Hereditary cancer-predisposing syndrome 2018-04-09 no assertion criteria provided clinical testing
Leiden Open Variation Database RCV000114503 SCV001192939 pathogenic Familial cancer of breast 2019-05-13 no assertion criteria provided curation Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Marc Tischkowitz.

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