Submissions for variant NM_024675.4(PALB2):c.940C>T (p.Gln314Ter)

gnomAD frequency: 0.00001  dbSNP: rs786203821

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000167296	SCV000218139	pathogenic	Hereditary cancer-predisposing syndrome	2022-04-05	criteria provided, single submitter	clinical testing	The p.Q314* pathogenic mutation (also known as c.940C>T), located in coding exon 4 of the PALB2 gene, results from a C to T substitution at nucleotide position 940. This changes the amino acid from a glutamine to a stop codon within coding exon 4. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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	RCV000463323	SCV000550759	pathogenic	Familial cancer of breast	2023-09-19	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln314*) 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 not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PALB2-related conditions. ClinVar contains an entry for this variant (Variation ID: 187557). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000523563	SCV000618328	pathogenic	not provided	2018-05-17	criteria provided, single submitter	clinical testing	This variant is denoted PALB2 c.940C>T at the cDNA level and p.Gln314Ter (Q314X) at the proteinlevel. The substitution creates a nonsense variant, which changes a Glutamine to a premature stop codon (CAA>TAA),and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNAdecay. Although this variant has not, to our knowledge, been reported in the literature, it is considered pathogenic
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000586368	SCV000699616	likely pathogenic	Hereditary breast ovarian cancer syndrome	2017-06-16	criteria provided, single submitter	clinical testing	Variant summary: The PALB2 c.940C>T (p.Gln314X) variant results in a premature termination codon, predicted to cause a truncated or absent PALB2 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 (e.g. c.2167_2167delAT, c.2920_2921delAA, p.Trp1038X, etc.). This variant is absent in 121222 control chromosomes from ExAC. Multiple clinical diagnostic laboratories (via ClinVar) have classified this variant as pathogenic. The variant of interest has not, to our knowledge, been reported in affected individuals via publications. Taken together, this variant is classified as likely pathogenic.
Counsyl	RCV000463323	SCV000785819	likely pathogenic	Familial cancer of breast	2017-12-11	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000167296	SCV000905194	pathogenic	Hereditary cancer-predisposing syndrome	2023-03-16	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 4 of the PALB2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in one individual affected with urothelial cancer (PMID: 31794323) and in a breast cancer case-control meta-analysis in 1/60466 cases and 0/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID PALB2_011108). 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 (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000523563	SCV002010950	pathogenic	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000463323	SCV004019150	pathogenic	Familial cancer of breast	2023-03-30	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
Baylor Genetics	RCV000463323	SCV004202125	pathogenic	Familial cancer of breast	2023-08-18	criteria provided, single submitter	clinical testing