Submissions for variant NM_024675.4(PALB2):c.206A>T (p.His69Leu)

gnomAD frequency: 0.00001  dbSNP: rs749443090

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000476673	SCV000550715	uncertain significance	Familial cancer of breast	2024-12-24	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 69 of the PALB2 protein (p.His69Leu). 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: 410167). 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 tolerated. 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.
GeneDx	RCV000485056	SCV000566416	uncertain significance	not provided	2023-04-22	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; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 19369211, 20871615)
Ambry Genetics	RCV000569594	SCV000663307	uncertain significance	Hereditary cancer-predisposing syndrome	2024-01-26	criteria provided, single submitter	clinical testing	The p.H69L variant (also known as c.206A>T), located in coding exon 3 of the PALB2 gene, results from an A to T substitution at nucleotide position 206. The histidine at codon 69 is replaced by leucine, an amino acid with similar properties. This amino acid position is not well 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	RCV000569594	SCV000690826	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-04	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with leucine at codon 69 of the PALB2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with PALB2-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000485056	SCV002046838	uncertain significance	not provided	2021-04-01	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000569594	SCV002530666	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-16	criteria provided, single submitter	curation
Fulgent Genetics, Fulgent Genetics	RCV005018787	SCV005646505	uncertain significance	Fanconi anemia complementation group N; Pancreatic cancer, susceptibility to, 3; Breast-ovarian cancer, familial, susceptibility to, 5	2024-03-16	criteria provided, single submitter	clinical testing