ClinVar Miner

Submissions for variant NM_024675.3(PALB2):c.2386G>T (p.Gly796Ter) (rs180177112)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129116 SCV000183831 pathogenic Hereditary cancer-predisposing syndrome 2019-01-10 criteria provided, single submitter clinical testing The p.G796* pathogenic mutation (also known as c.2386G>T), located in coding exon 5 of the PALB2 gene, results from a G to T substitution at nucleotide position 2386. This changes the amino acid from a glycine to a stop codon within coding exon 5. This alteration has been detected in multiple breast cancer patients and families (Rahman N et al. Nat. Genet. 2007 Feb;39:165-7; Antoniou AC et al. N. Engl. J. Med. 2014 Aug;371:497-506; Li YT et al. Eur. J. Med. Res. 2015 Oct;20:85; Lee JEA et al. J. Pathol. 2018 May;245(1):53-60). It was also seen in a patient with pancreatic cancer (Shindo K et al. J. Clin. Oncol. 2017 Oct;35(30):3382-3390). 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 RCV000114524 SCV000218974 pathogenic Familial cancer of breast 2020-10-05 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gly796*) 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 observed in multiple individuals with breast cancer (PMID: 17200668, 23935381, 24549055, 25099575, 24415441). ClinVar contains an entry for this variant (Variation ID: 126649). Loss-of-function variants in PALB2 are known to be pathogenic (PMID: 25099575, 17200668). For these reasons, this variant has been classified as Pathogenic.
Cancer Genetics Laboratory,Peter MacCallum Cancer Centre RCV000114524 SCV000267967 likely pathogenic Familial cancer of breast 2015-06-01 criteria provided, single submitter case-control
GeneDx RCV000236024 SCV000292656 pathogenic not provided 2018-05-16 criteria provided, single submitter clinical testing This pathogenic variant is denoted PALB2 c.2386G>T at the cDNA level and p.Gly796Ter (G796X) at the protein level. The substitution creates a nonsense variant, which changes a Glycine to a premature stop codon (GGA>TGA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been reported in association with breast cancer (Rahman 2007, Casadei 2011, Fernandes 2014) and is considered pathogenic.
Counsyl RCV000114524 SCV000488542 pathogenic Familial cancer of breast 2016-04-20 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000236024 SCV000601759 pathogenic not provided 2017-04-13 criteria provided, single submitter clinical testing
Color Health, Inc RCV000129116 SCV000685947 pathogenic Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000236024 SCV000807087 pathogenic not provided 2017-05-01 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000114524 SCV001362314 pathogenic Familial cancer of breast 2019-09-23 criteria provided, single submitter clinical testing Variant summary: PALB2 c.2386G>T (p.Gly796X) 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 4e-06 in 251426 control chromosomes (gnomAD). c.2386G>T has been reported in the literature in multiple individuals affected with Breast Cancer (Antoniou_2014, Castera_2014, Fernandes_2014). 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. Eight ClinVar submissions (evaluation after 2014) cite the variant seven times as pathogenic and once as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Leiden Open Variation Database RCV000114524 SCV001193221 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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