Submissions for variant NM_024675.4(PALB2):c.18G>T (p.Gly6=)

dbSNP: rs587782462

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131549	SCV000186549	likely pathogenic	Hereditary cancer-predisposing syndrome	2024-05-27	criteria provided, single submitter	clinical testing	The c.18G>T variant (also known as p.G6G), located in coding exon 1, results from a G to T substitution at nucleotide position 18 of the PALB2 gene. This nucleotide substitution does not change the amino acid at codon 6. This alteration was identified in a patient with thyroid cancer at 25 and pancreatic cancer at 55, and a family history of breast and pancreatic cancer (Yang C et al. Breast Cancer Res. Treat. 2018 Sep; Epub ahead of print). This alteration was detected in 2/5589 German BRCA1/2-negative probands with breast cancer (Hauke J et al. Cancer Med. 2018 04;7:1349-1358) and in a woman with breast cancer diagnosed at age 31 (Kuemmel S et al. NPJ Breast Cancer. 2020 Jul;6:31). RNA analyses have shown that this alteration creates a cryptic splice donor site resulting in a deletion of part of exon 1, a reading frame shift, and a premature stop codon (p.G6Vfs*26) (Yang C et al. Breast Cancer Res. Treat. 2018 Sep; Ambry internal data). In silico splice site analysis predicts that this alteration will weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
GeneDx	RCV000432017	SCV000525381	likely pathogenic	not provided	2023-12-04	criteria provided, single submitter	clinical testing	Exonic variant demonstrated to result in aberrant splicing leading to a predicted null allele in a gene for which loss-of-function is a known mechanism of disease (PMID: 30255452); In silico analysis supports a deleterious effect on splicing; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29522266, 30441849, 32728620, 30255452)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000557471	SCV000633312	pathogenic	Familial cancer of breast	2024-10-21	criteria provided, single submitter	clinical testing	This sequence change affects codon 6 of the PALB2 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the PALB2 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or altered protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with pancreatic, thyroid, and/or breast cancer (PMID: 30255452, 32728620). ClinVar contains an entry for this variant (Variation ID: 142432). Studies have shown that this variant results in activation of a cryptic splice site, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 30255452; internal data). For these reasons, this variant has been classified as Pathogenic.
Diagnostic Molecular Genetics Laboratory, Memorial Sloan Kettering Cancer Center	RCV000557471	SCV000863527	likely pathogenic	Familial cancer of breast	2018-12-14	criteria provided, single submitter	clinical testing	Experimental study demonstrated that this variant leads to aberrant splicing and deletion of the 3' end of exon 1. It is predicted to lead to a truncated or absent protein (PMID: 30255452). This variant is classified as likely pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002265620	SCV000919939	likely pathogenic	Hereditary breast ovarian cancer syndrome	2022-05-14	criteria provided, single submitter	clinical testing	Variant summary: PALB2 c.18G>T alters a non-conserved nucleotide resulting in a synonymous change. Several computational tools predict a significant impact on normal splicing: Five predict the variant creates a novel exonic 5' splice donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing leading to a deletion of 32 base pairs in exon 1, which leads to a frameshift and truncated protein (Yang_2019). The variant was absent in 247932 control chromosomes. c.18G>T has been reported in the literature as a VUS in an individual from a cohort of unselected individuals with Ovarian Cancer (Koczkowska_2018), in a proband with pancreatic and throid cancers and a family history of pancreatic and breast cancers (Yang_2019) and in a woman with ER+/PR+/HER2- high grade invasive breast cancer concurrent with ductal carcinoma in situ (DCIS) (Kuemmel_2020). These data indicate that the variant may be associated with disease. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 (Likely pathogenic, n=3; VUS, n=1). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely pathogenic.
MGZ Medical Genetics Center	RCV000557471	SCV002579178	likely pathogenic	Familial cancer of breast	2022-04-14	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000432017	SCV002774285	pathogenic	not provided	2023-04-24	criteria provided, single submitter	clinical testing	The PALB2 c.18G>T (p.Gly6=) synonymous variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database (http://gnomad.broadinstitute.org)). In the published literature, this variant has been identified in individuals with breast and ovarian cancer (PMIDs: 32728620 (2020), 30441849 (2018), 29522266 (2018)), and to segregate with disease in a family with pancreatic, thyroid, and breast cancer (PMID: 30255452 (2019)). Experimental studies indicated this variant disrupted PALB2 mRNA splicing, resulting in a frameshift and premature termination of PALB2 protein synthesis (PMID: 30255452 (2019)). Based on the available information, this variant is classified as pathogenic.
Myriad Genetics, Inc.	RCV000557471	SCV004188442	likely pathogenic	Familial cancer of breast	2023-09-05	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. mRNA analysis has demonstrated abnormal mRNA splicing occurs [Myriad internal data].
Baylor Genetics	RCV000557471	SCV004202107	pathogenic	Familial cancer of breast	2023-08-30	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000432017	SCV004242706	likely pathogenic	not provided	2024-02-06	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131549	SCV004358011	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-03-22	criteria provided, single submitter	clinical testing	This synonymous variant causes a G>T nucleotide change in exon 1 of the PALB2 gene. Splice site prediction tools indicate that this variant may activate a cryptic splice donor site 31 nucleotides upstream of the native intron 1 splice donor site. A functional RNA study has shown that this cryptic donor site is used, resulting in a complete disruption of normal splicing in the mutant allele (PMID: 30255452). Among several abnormal transcripts produced from the mutant allele, the major abnormal transcript resulted in a deletion of 32 base pairs in exon 1 and frameshift (r.17_48del; p.Gly6Valfs*26). This variant was observed in an individual affected with pancreatic and thyroid cancers at 55 and 25 years old, respectively, with family history of breast, pancreatic and other cancers in multiple relatives (PMID: 30255452). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of PALB2 function is a known mechanism of disease. Based on the available evidence, this variant is classified as Likely Pathogenic.
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000432017	SCV005197097	likely pathogenic	not provided	2022-07-19	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000432017	SCV001808679	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000432017	SCV001906076	likely pathogenic	not provided		no assertion criteria provided	clinical testing