Submissions for variant NM_024675.4(PALB2):c.196C>T (p.Gln66Ter)

gnomAD frequency: 0.00001  dbSNP: rs180177083

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000163078	SCV000213579	pathogenic	Hereditary cancer-predisposing syndrome	2024-09-13	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 individuals and 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; Nguyen-Dumont T et al. BMC Med Genomics, 2013 Nov;6:48; Antoniou AC et al. N Engl J Med, 2014 Aug;371:497-506; Thompson ER et al. Breast Cancer Res, 2015 Aug;17:111; Li J et al. J Med Genet, 2016 Jan;53:34-42; Thompson ER et al. J Clin Oncol, 2016 May;34:1455-9; Woodward ER et al. Genet Med, 2021 Jun; Dorling et al. N Engl J Med. 2021 02;384:428-439). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000114503	SCV000253937	pathogenic	Familial cancer of breast	2024-01-26	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. Loss-of-function variants in PALB2 are known to be pathogenic (PMID: 17200668, 17200671, 17200672, 24136930, 25099575). This variant is present in population databases (rs180177083, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with breast and ovarian cancer (PMID: 21285249, 21409391, 23448497, 26534844). ClinVar contains an entry for this variant (Variation ID: 126629). 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	2023-11-09	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 significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; 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, 32853339, 34308104, 33763779, 33113089, 28888541, 34113003, 29922827, 33471991)
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	2021-03-30	criteria provided, single submitter	clinical testing	This nonsense variant causes the premature termination of PALB2 protein synthesis. In addition, it has been reported in individuals and families affected with breast and/or ovarian cancer in the published literature (PMIDs: 21285249 (2011), 21409391 (2011), 23448497 (2013), 26534844 (2016), 27878467 (2016), and 28779002 (2017)). Based on the available information, this variant is classified as pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000163078	SCV000685912	pathogenic	Hereditary cancer-predisposing syndrome	2023-05-10	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, 34113003). This variant has been detected in a breast cancer case-control meta-analysis in 4/60466 cases and 1/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID PALB2_010022). 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 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
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798296	SCV002043590	pathogenic	Breast and/or ovarian cancer	2020-02-21	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000114503	SCV004019635	pathogenic	Familial cancer of breast	2023-03-31	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	RCV000114503	SCV004202601	pathogenic	Familial cancer of breast	2024-03-02	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000235795	SCV005414343	likely pathogenic	not provided	2023-10-30	criteria provided, single submitter	clinical testing	PM2, PVS1
Fulgent Genetics, Fulgent Genetics	RCV005016383	SCV005646506	pathogenic	Fanconi anemia complementation group N; Pancreatic cancer, susceptibility to, 3; Breast-ovarian cancer, familial, susceptibility to, 5	2024-03-07	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.