Submissions for variant NM_024675.4(PALB2):c.101G>T (p.Arg34Leu)

dbSNP: rs144944814

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000166587	SCV000217391	uncertain significance	Hereditary cancer-predisposing syndrome	2024-09-24	criteria provided, single submitter	clinical testing	The p.R34L variant (also known as c.101G>T), located in coding exon 2 of the PALB2 gene, results from a G to T substitution at nucleotide position 101. The arginine at codon 34 is replaced by leucine, an amino acid with dissimilar properties. This alteration has been reported with a carrier frequency of 0.0000 in 53 unselected men with breast cancer and 0.0001 in 12490 male controls of Japanese ancestry (Momozawa Y et al. Nat Commun, 2018 10;9:4083). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000456690	SCV000550724	uncertain significance	Familial cancer of breast	2024-11-21	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 34 of the PALB2 protein (p.Arg34Leu). This variant is present in population databases (rs144944814, gnomAD 0.02%). 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: 186920). 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.
GeneDx	RCV000520497	SCV000618000	uncertain significance	not provided	2024-01-10	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: 30287823, 20871615, 19369211, 36243179)
Color Diagnostics, LLC DBA Color Health	RCV000166587	SCV001342663	uncertain significance	Hereditary cancer-predisposing syndrome	2022-08-23	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with leucine at codon 34 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 been reported in breast, pancreatic and prostate cancer case-control studies in which it was detected in 1 unaffected individual in each study and absent in cancer cases (PMID: 30287823, 31214711, 32980694). This variant has been identified in 5/282888 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.
Sema4, Sema4	RCV000166587	SCV002530578	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-23	criteria provided, single submitter	curation
Fulgent Genetics, Fulgent Genetics	RCV002498826	SCV002800140	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group N; Pancreatic cancer, susceptibility to, 3	2022-04-14	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000456690	SCV004202040	uncertain significance	Familial cancer of breast	2023-10-14	criteria provided, single submitter	clinical testing
Leiden Open Variation Database	RCV000520497	SCV001192925	uncertain significance	not provided	2018-08-25	no assertion criteria provided	curation	Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Yukihide Momozawa.