Submissions for variant NM_024675.4(PALB2):c.298C>T (p.Leu100Phe)

gnomAD frequency: 0.00021  dbSNP: rs61756147

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212772	SCV000150004	uncertain significance	not provided	2023-10-04	criteria provided, single submitter	clinical testing	Not found to have a statistically significant association with breast cancer risk in a multi-ethnic exome array study (Haiman et al., 2013); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24448499, 25479140, 26283626, 21409391, 26315354, 25225577, 25186627, 26976419, 27060149, 26689913, 28767289, 28779002, 32659497, 32546565, 28259476, 35263119, 30541756, 28873162, 32885271, 33471991, 20871615, 19369211, 23555315, 34326862)
Invitae	RCV000114577	SCV000166659	likely benign	Familial cancer of breast	2024-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000116095	SCV000172824	likely benign	Hereditary cancer-predisposing syndrome	2022-09-26	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Cancer Genetics Laboratory, Peter MacCallum Cancer Centre	RCV000114577	SCV000267982	uncertain significance	Familial cancer of breast	2015-06-01	criteria provided, single submitter	case-control
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212772	SCV000889593	uncertain significance	not provided	2023-04-17	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.00033 (42/129102 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals affected with breast and/or ovarian cancer (PMIDs: 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/PALB2), 25225577 (2014), 26315354 (2015), 26976419 (2016), 28767289 (2017), and 28873162 (2017)). This variant has also been identified in healthy, unaffected individuals (PMIDs: 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/PALB2), 26283626 (2015)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Color Diagnostics, LLC DBA Color Health	RCV000116095	SCV000910613	likely benign	Hereditary cancer-predisposing syndrome	2020-12-10	criteria provided, single submitter	clinical testing
Mendelics	RCV000114577	SCV001140056	uncertain significance	Familial cancer of breast	2019-05-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001119843	SCV001278289	uncertain significance	Fanconi anemia complementation group N	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001192907	SCV001361355	likely benign	not specified	2023-01-09	criteria provided, single submitter	clinical testing	Variant summary: PALB2 c.298C>T (p.Leu100Phe) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00018 in 293556 control chromosomes (gnomAD and publication data), predominantly at a frequency of 0.00033 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in PALB2 causing Hereditary Breast and Ovarian Cancer Syndrome phenotype (0.00016), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. In addition, this variant has been also reported in 3/7325 European American women who were older than age 70 years and cancer free (in the FLOSSIES database). c.298C>T has been reported in the literature in individuals affected with different types of cancer (Wong 2011, Haiman 2013, Hartley 2014, Tung 2014, Grant 2015, Ramus 2015, Lu 2015, Shindo 2017, Seligson_2019), but was also found in healthy controls (Thompson 2015, Ramus 2015). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Co-occurrence with another pathogenic variant has been reported (BRCA1 c.5266dupC (p.Gln1756Profs*74), Tung 2014), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported.12 clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified as VUS (n=6), Likely Benign (n=5) and Benign (n=1). Based on the evidence outlined above, the variant was classified as likely benign.
Sema4, Sema4	RCV000116095	SCV002530742	likely benign	Hereditary cancer-predisposing syndrome	2021-05-08	criteria provided, single submitter	curation
PreventionGenetics, part of Exact Sciences	RCV003415878	SCV004108701	uncertain significance	PALB2-related condition	2023-05-25	criteria provided, single submitter	clinical testing	The PALB2 c.298C>T variant is predicted to result in the amino acid substitution p.Leu100Phe. This variant has been detected in patients with breast and ovarian cancer (Wong et al. 2011. PubMed ID: 21409391; Tung et al. 2016. PubMed ID: 26976419, Table A2; Hartley et al. 2014. PubMed ID: 25225577, Table S4; Ramus et al. 2015. PubMed ID: 26315354 Sup. Table 4; Kanchi et al. 2014. PubMed ID: 24448499, sup data 8) and pancreatic cancer (Shindo et al. 2017. PubMed ID: 28767289, referred to as c.298G>A; Grant et al. 2015. PubMed ID: 25479140, Sup. Table 1). However, it was detected in an equal number of cases and controls (2) in one of these studies (Ramus et al. 2015. PubMed ID: 26315354 Sup. Table 4). This variant is documented in the gnomAD general population database with a minor allele frequency of ~0.03% among non-Finnish Europeans (https://gnomad.broadinstitute.org/variant/16-23647569-G-A) and has conflicting interpretations in ClinVar ranging from benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/126698/).The amino acid substitution prediction programs MutationTaster, PolyPhen-2, and SIFT predict the p.Leu100Phe change to be a “polymorphism,” “benign,” and “tolerated,” respectively (Alamut Visual v2.11). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492442	SCV004239559	uncertain significance	Breast and/or ovarian cancer	2022-12-21	criteria provided, single submitter	clinical testing
GenomeConnect, ClinGen	RCV000212772	SCV000784703	not provided	not provided		flagged submission	phenotyping only	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
True Health Diagnostics	RCV000116095	SCV000805278	likely benign	Hereditary cancer-predisposing syndrome	2018-06-18	no assertion criteria provided	clinical testing
Leiden Open Variation Database	RCV000212772	SCV001192960	uncertain significance	not provided	2019-05-13	no assertion criteria provided	curation	Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitters to LOVD: Marc Tischkowitz, Melissa DeRycke.
GenomeConnect, ClinGen	RCV001249253	SCV001423193	not provided	Fanconi anemia complementation group N; Hereditary cancer-predisposing syndrome		no assertion provided	phenotyping only	Variant interpretted as Uncertain significance and reported on 09-21-2019 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355228	SCV001550052	uncertain significance	Pancreatic cancer, susceptibility to, 3		no assertion criteria provided	clinical testing	The PALB2 p.Leu100Phe variant was identified in 5 of 11930 proband chromosomes (frequency: 0.0004) from American, Canadian and Australian individuals or families with BRCA1/2 negative breast cancer, familial breast or breast/ovarian cancer, or ovarian cancer and was present in 4 of 10858 control chromosomes (frequency: 0.0003) from healthy individuals (Ramus_2015_26315354, Thompson_2015_26283626, Tung_2016_26976419, Wong_2011_21409391, Hartley_2014_25225577). The variant was identified in the following databases: dbSNP (ID: rs61756147) “With Uncertain significance allele”, ClinVar (classified uncertain significance by GeneDx, Invitae, Ambry Genetics, Cancer Genetics Laboratory (Peter MacCallum Cancer Center) and the PALB2 database), Clinvitae (3x), LOVD 3.0 (1x), Zhejiang Colon Cancer Database (1x), and in control databases in 46 of 277092 chromosomes at a frequency of 0.0002 (Genome Aggregation Database Feb 27, 2017). Observation by population include “Other” in 1 of 6464 chromosomes (freq: 0.0002), Latino in 1 of 34398 chromosomes (freq: 0.00003), European Non-Finnish in 42 of 126642 chromosomes (freq: 0.0003), and European Finnish in 2 of 25786 chromosomes (freq: 0.00008); it was not observed in the African, Ashkenazi Jewish, East Asian, and South Asian populations. The variant was not identified in Cosmic or MutDB. The p.Leu100 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of the variant Phe impacts the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000116095	SCV002506609	benign	Hereditary cancer-predisposing syndrome	2022-03-10	no assertion criteria provided	clinical testing