Submissions for variant NM_024675.4(PALB2):c.205C>T (p.His69Tyr)

dbSNP: rs879253891

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000236918	SCV000292644	uncertain significance	not provided	2023-04-24	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individual(s) with breast and/or ovarian cancer (Kwong et al., 2020); This variant is associated with the following publications: (PMID: 35230528, 32068069)
Ambry Genetics	RCV000575557	SCV000670607	uncertain significance	Hereditary cancer-predisposing syndrome	2022-06-30	criteria provided, single submitter	clinical testing	The p.H69Y variant (also known as c.205C>T), located in coding exon 3 of the PALB2 gene, results from a C to T substitution at nucleotide position 205. The histidine at codon 69 is replaced by tyrosine, an amino acid with similar properties. This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000575557	SCV000690825	uncertain significance	Hereditary cancer-predisposing syndrome	2019-05-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781688	SCV000919940	uncertain significance	not specified	2022-06-20	criteria provided, single submitter	clinical testing	Variant summary: PALB2 c.205C>T (p.His69Tyr) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251470 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.205C>T has been reported in the literature as a VUS in settings of multigene panel testing in at-least one individual affected with BRCA-negative Breast and/or Ovarian Cancer (example, Kwong_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae	RCV000823428	SCV000964288	uncertain significance	Familial cancer of breast	2024-01-13	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 69 of the PALB2 protein (p.His69Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 32068069, 34326862). ClinVar contains an entry for this variant (Variation ID: 245654). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000236918	SCV002774677	uncertain significance	not provided	2021-06-19	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002494677	SCV002794331	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group N; Pancreatic cancer, susceptibility to, 3	2021-08-25	criteria provided, single submitter	clinical testing