Submissions for variant NM_024675.4(PALB2):c.2750T>C (p.Val917Ala)

gnomAD frequency: 0.00001  dbSNP: rs763645981

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000215127	SCV000275539	uncertain significance	Hereditary cancer-predisposing syndrome	2024-12-05	criteria provided, single submitter	clinical testing	The p.V917A variant (also known as c.2750T>C), located in coding exon 8 of the PALB2 gene, results from a T to C substitution at nucleotide position 2750. The valine at codon 917 is replaced by alanine, an amino acid with similar properties. This alteration has been identified in multiple individuals diagnosed with breast cancer (Hellebrand H et al. Hum Mutat, 2011 Jun;32:E2176-88; Hauke J et al. Cancer Med, 2018 04;7:1349-1358). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000533162	SCV000633373	uncertain significance	Familial cancer of breast	2025-01-21	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 917 of the PALB2 protein (p.Val917Ala). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with breast cancer (PMID: 21618343, 30303537, 34846068). ClinVar contains an entry for this variant (Variation ID: 231633). 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	RCV000215127	SCV000690872	uncertain significance	Hereditary cancer-predisposing syndrome	2019-11-18	criteria provided, single submitter	clinical testing	This missense variant replaces valine with alanine at codon 917 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with breast cancer (PMID: 21618343). This variant has also been identified in 1/249522 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.
Baylor Genetics	RCV000533162	SCV004202158	uncertain significance	Familial cancer of breast	2023-07-26	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001358536	SCV001554298	uncertain significance	Carcinoma of colon		no assertion criteria provided	clinical testing	The PALB2 p.Val917Ala variant was identified in 1 of 1636 proband chromosomes (frequency: 0.0006) from individuals or families with breast or ovarian cancer (Hellebrand 2011). The variant was identified in dbSNP (rs763645981) as “with uncertain significance allele”, ClinVar (classified as uncertain significance by Invitae, Ambry Genetics and Color) and LOVD 3.0 (observed 7x). The variant was identified in control databases in 1 of 249,522 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European population in 1 of 112,524 chromosomes (freq: 0.000009); it was not observed in the African, Latino, Ashkenazi Jewish, East Asian, Finnish, Other or South Asian populations. The p.Val917 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The p.Val917Ala variant occurs in the first base of the exon. This position has been shown to be part of the splicing consensus sequence and variants involving this position sometimes affect splicing. In addition, 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predicts a greater than 10% difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.