Submissions for variant NM_024675.4(PALB2):c.2417C>T (p.Pro806Leu)

gnomAD frequency: 0.00002  dbSNP: rs45464991

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129403	SCV000184171	likely benign	Hereditary cancer-predisposing syndrome	2018-05-16	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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.
Invitae	RCV000204760	SCV000262053	uncertain significance	Familial cancer of breast	2024-01-19	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 806 of the PALB2 protein (p.Pro806Leu). This variant is present in population databases (rs45464991, gnomAD 0.004%). This missense change has been observed in individual(s) with breast cancer (PMID: 17200668, 26283626). ClinVar contains an entry for this variant (Variation ID: 141063). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PALB2 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Cancer Genetics Laboratory, Peter MacCallum Cancer Centre	RCV000204760	SCV000268013	uncertain significance	Familial cancer of breast	2015-06-01	criteria provided, single submitter	case-control
GeneDx	RCV000235688	SCV000292987	uncertain significance	not provided	2023-08-22	criteria provided, single submitter	clinical testing	Observed in an individual with familial pancreatic cancer who also harbored a truncating PALB2 variant (Zhen et al., 2014); while phase was not described in this publication, internal data suggests that these variants are in cis; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in both breast or biliary tract cancer cases and healthy controls in large case-control studies (Rahman et al., 2007; Thompson et al., 2015; Decker et al., 2017; Momozawa et al., 2018; Okawa et al., 2023); This variant is associated with the following publications: (PMID: 17200668, 28779002, 26283626, 30287823, 24485656, 36243179, 25356972)
Counsyl	RCV000204760	SCV000784825	uncertain significance	Familial cancer of breast	2016-12-29	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129403	SCV000910938	benign	Hereditary cancer-predisposing syndrome	2016-07-11	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001192769	SCV001361097	uncertain significance	not specified	2019-01-29	criteria provided, single submitter	clinical testing	Variant summary: PALB2 c.2417C>T (p.Pro806Leu) 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 2.9e-05 in 272736 control chromosomes (gnomAD and publications). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2417C>T has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer and pancreatic cancer (Decker_2017, Zhen_2015, Rahman_2007, Thompson_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrences with other pathogenic variants have been reported (PALB2 c.2509G>T, p.E837X; in Zhen_2015 and in an internal sample), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant four times as uncertain significance and once as likely benign. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149891	SCV003838715	uncertain significance	Breast and/or ovarian cancer	2021-08-31	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000204760	SCV004019648	likely benign	Familial cancer of breast	2023-03-31	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV001192769	SCV004242687	uncertain significance	not specified	2024-02-06	criteria provided, single submitter	clinical testing
Leiden Open Variation Database	RCV001030305	SCV001193224	uncertain significance	Pancreatic cancer, susceptibility to, 3	2019-05-13	no assertion criteria provided	curation	Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitters to LOVD: Marc Tischkowitz, Yukihide Momozawa.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355012	SCV001549766	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The PALB2 p.Pro806Leu variant was identified in 3 of 7292 proband chromosomes (frequency: 0.0004) from individuals or families with BRCA1/2 negative breast cancer, familial pancreatic cancer or familial breast cancer, and was present in 1 of 3996 control chromosomes frequency:0.0003) from healthy individuals (Thompson 2015, Zhen 2015, Rahman 2007). In the proband with familial pancreatic cancer, the variant co-occurred with a truncating pathogenic PALB2 variant (E837X, 2509G>T)) (Zhen 2015). The variant was also identified in dbSNP (ID: rs45464991) “With Uncertain significance allele”, ClinVar (classified with conflicting interpretations of pathogenicity; submitters: likely benign by Ambry Genetics and uncertain significance by Invitae, GeneDx, Counsyl and Cancer Genetics Laboratory (Peter MacCallum Cancer Centre)), and Zhejiang University Database (1X). The variant was identified in control databases in 6 of 246258 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017), observed in the following populations: European (Non-Finnish) in 4 of 111710 chromosomes (freq: 0.00004), South Asian in 1 of 30782 chromosomes (freq: 0.00003) and Latino in 1 of 33582 chromosomes (freq: 0.00003), while not observed in the African, Ashkenazi Jewish, East Asian, European (Finnish), and Other populations. The p.Pro806Leu residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to 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) 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.