Submissions for variant NM_024675.4(PALB2):c.3451C>T (p.Leu1151Phe)

gnomAD frequency: 0.00001  dbSNP: rs786203462

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000166777	SCV000217590	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-10	criteria provided, single submitter	clinical testing	The p.L1151F variant (also known as c.3451C>T), located in coding exon 13 of the PALB2 gene, results from a C to T substitution at nucleotide position 3451. The leucine at codon 1151 is replaced by phenylalanine, an amino acid with highly similar properties. This amino acid position is highly 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.
GeneDx	RCV000587507	SCV000565357	uncertain significance	not provided	2021-08-11	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek 2016); 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: 19609323, 20871615, 24485656)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000587507	SCV000699594	uncertain significance	not provided	2016-08-01	criteria provided, single submitter	clinical testing	Variant summary: The PALB2 c.3451C>T (p.Leu1151Phe) variant involves the alteration of a conserved nucleotide. 3/5 in silico tools predict a damaging outcome. This variant is absent in 121358 control chromosomes. One clinical diagnostic laboratories has classified this variant as VUS. The variant of interest has not, to our knowledge, been reported in affected individuals via publications nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant was classified as a variant of uncertain significance (VUS) until additional information becomes available.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000816063	SCV000956552	uncertain significance	Familial cancer of breast	2024-01-30	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 1151 of the PALB2 protein (p.Leu1151Phe). This variant is present in population databases (rs786203462, gnomAD 0.002%). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 35610400). ClinVar contains an entry for this variant (Variation ID: 187089). 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.
Color Diagnostics, LLC DBA Color Health	RCV000166777	SCV001354178	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-16	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with phenylalanine at codon 1151 of the PALB2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with pancreatic cancer (PMID: 35456488). This variant has been identified in 2/251472 chromosomes 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.
Fulgent Genetics, Fulgent Genetics	RCV002485036	SCV002790893	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group N; Pancreatic cancer, susceptibility to, 3	2022-03-08	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000816063	SCV004202635	uncertain significance	Familial cancer of breast	2023-05-16	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000587507	SCV005092465	uncertain significance	not provided	2024-07-01	criteria provided, single submitter	clinical testing	PALB2: PM2, PS4:Supporting, BP1, BP4