Submissions for variant NM_024675.4(PALB2):c.3367G>A (p.Val1123Met)

dbSNP: rs757118000

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164958	SCV000215649	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-25	criteria provided, single submitter	clinical testing	The p.V1123M variant (also known as c.3367G>A), located in coding exon 13 of the PALB2 gene, results from a G to A substitution at nucleotide position 3367. The valine at codon 1123 is replaced by methionine, an amino acid with highly similar properties. This alteration was identified in 1/1996 high risk Australian breast cancer patients and 0/1998 unaffected controls (Thompson ER et al. Breast Cancer Res., 2015 Aug;17:111). It has also been reported in patients with ovarian and colorectal cancers (Kraus C et al. Int. J. Cancer, 2017 Jan;140:95-102; Raskin L et al. Oncotarget, 2017 Nov;8:93450-93463) and it was identified in a cohort of 3,579 African male prostate cancer cases and controls who underwent multi-gene panel testing of 19 DNA repair and cancer predisposition genes (Matejcic M et al. JCO Precis Oncol 2020 Jan;4:32-43). In a homology-directed DNA repair (HDR) assay, this alteration was found to be functionally inconclusive and in a PARP inhibitor sensitivity assay, this alteration was found to be functionally normal (Boonen RACM et al. Nat Commun, 2019 11;10:5296). 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.
Cancer Genetics Laboratory, Peter MacCallum Cancer Centre	RCV000211079	SCV000268027	uncertain significance	Familial cancer of breast	2015-06-01	criteria provided, single submitter	case-control
Invitae	RCV000211079	SCV000550763	uncertain significance	Familial cancer of breast	2023-11-17	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 1123 of the PALB2 protein (p.Val1123Met). This variant is present in population databases (rs757118000, gnomAD 0.0009%). This missense change has been observed in individual(s) with breast cancer or breast and ovarian cancer and colon and bladder cancer (PMID: 26283626, 27616075, 29212164). ClinVar contains an entry for this variant (Variation ID: 185518). 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. Experimental studies have shown that this missense change does not substantially affect PALB2 function (PMID: 31757951). 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	RCV000479580	SCV000567863	uncertain significance	not provided	2015-09-03	criteria provided, single submitter	clinical testing	This variant is denoted PALB2 c.3367G>A at the cDNA level, p.Val1123Met (V1123M) at the protein level, and results in the change of a Valine to a Methionine (GTG>ATG). This variant has been observed in at least one individual with a history of breast cancer (Thompson 2015). PALB2 Val1123Met was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Valine and Methionine share similar properties, this is considered a conservative amino acid substitution. PALB2 Val1123Met occurs at a position that is conserved in mammals and is located in the WD 6 domain and a region responsible for interaction with RAD51, BRCA2, and POLH (UniProt). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether PALB2 Val1123Met is pathogenic or benign. We consider it to be a variant of uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000164958	SCV000690916	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-14	criteria provided, single submitter	clinical testing	This missense variant replaces valine with methionine at codon 1123 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). A functional study have reported that this variant has no impact on PALB2 function in homology-directed repair and PARP inhibitor resistance assays (PMID: 31757951). This variant has been reported in three individuals affected with breast cancer, breast and ovarian cancer, and colon and bladder cancer (PMID: 26283626, 27616075, 29212164). This variant has been identified in 2/251360 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	RCV002485022	SCV002782648	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group N; Pancreatic cancer, susceptibility to, 3	2022-05-28	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000211079	SCV004202083	uncertain significance	Familial cancer of breast	2023-09-13	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000479580	SCV004222340	uncertain significance	not provided	2023-01-18	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000008 (2/251360 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with breast/ovarian (PMIDs: 27616075 (2016, 26283626 (2015)) and colorectal cancer (PMID: 29212164 (2017)). Functional assays showed a reduction in homologous recombination, but no PARPi sensitivity (PMID: 31757951 (2019)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.