Submissions for variant NM_024675.4(PALB2):c.2755G>A (p.Val919Ile)

gnomAD frequency: 0.00002  dbSNP: rs775193384

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Cancer Genetics Laboratory, Peter MacCallum Cancer Centre	RCV000211057	SCV000268017	uncertain significance	Familial cancer of breast	2015-06-01	criteria provided, single submitter	case-control
Ambry Genetics	RCV000454132	SCV000538158	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-03	criteria provided, single submitter	clinical testing	The p.V919I variant (also known as c.2755G>A), located in coding exon 8 of the PALB2 gene, results from a G to A substitution at nucleotide position 2755. The valine at codon 919 is replaced by isoleucine, an amino acid with highly similar properties. This alteration has been reported in the literature in an Australian familial breast cancer cohort (Thompson ER et al. Breast Cancer Res. 2015 Aug;17:111). This alteration was also found to be functionally normal in a homology-directed DNA repair (HDR) assay (Wiltshire T et al. Genet Med, 2020 03;22:622-632). Additionally, this variant was reported in 4/60,466 breast cancer cases and in 2/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). 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	RCV000478723	SCV000566709	uncertain significance	not provided	2023-07-28	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast cancer as well as unaffected controls (Thompson et al., 2015; Dorling et al., 2021); Published functional studies using a cellular homology directed DNA repair (HDR) assay do not demonstrate a damaging effect (Wiltshire et al., 2020); This variant is associated with the following publications: (PMID: 26283626, 33471991, 35762214, 31636395)
Color Diagnostics, LLC DBA Color Health	RCV000454132	SCV000685975	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-22	criteria provided, single submitter	clinical testing	This missense variant replaces valine with isoleucine at codon 919 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 has shown that this variant has neutral impact on homology-directed DNA repair activity (PMID: 31636395). This variant has been detected in a breast cancer case-control meta-analysis in 4/60466 cases and 2/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID PALB2_010695). This variant has been identified in 4/249880 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.
Invitae	RCV000211057	SCV000757149	uncertain significance	Familial cancer of breast	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 919 of the PALB2 protein (p.Val919Ile). This variant is present in population databases (rs775193384, gnomAD 0.004%). 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: 225856). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PALB2 protein function with a negative predictive value of 80%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on PALB2 function (PMID: 31636395, 35762214). 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.
CeGaT Center for Human Genetics Tuebingen	RCV000478723	SCV002545766	uncertain significance	not provided	2022-05-01	criteria provided, single submitter	clinical testing	PALB2: PM2, BP4, BS3:Supporting
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002465567	SCV002760824	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003150103	SCV003838710	uncertain significance	Breast and/or ovarian cancer	2023-06-23	criteria provided, single submitter	clinical testing
Integrative Tumor Epidemiology Branch, National Institutes of Health	RCV002266935	SCV002549702	uncertain significance	Chordoma	2021-03-22	no assertion criteria provided	research	Modestly reduce HRR activity and BRCA2 binding