Submissions for variant NM_024675.4(PALB2):c.968C>T (p.Ala323Val)

dbSNP: rs730881882

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000564210	SCV000666901	uncertain significance	Hereditary cancer-predisposing syndrome	2019-10-22	criteria provided, single submitter	clinical testing	The p.A323V variant (also known as c.968C>T), located in coding exon 4 of the PALB2 gene, results from a C to T substitution at nucleotide position 968. The alanine at codon 323 is replaced by valine, an amino acid with similar properties. 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	RCV000635863	SCV000757288	uncertain significance	Familial cancer of breast	2024-10-02	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 323 of the PALB2 protein (p.Ala323Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 31206626). ClinVar contains an entry for this variant (Variation ID: 482023). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt PALB2 protein function with a negative predictive value of 80%. 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001800781	SCV002047139	uncertain significance	not provided	2021-05-21	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002476232	SCV002792865	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group N; Pancreatic cancer, susceptibility to, 3	2021-07-24	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000564210	SCV004357953	uncertain significance	Hereditary cancer-predisposing syndrome	2022-08-29	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with valine at codon 323 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 an individual affected with breast cancer (PMID: 31206626). This variant has not been identified 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004586802	SCV005076453	uncertain significance	not specified	2024-04-30	criteria provided, single submitter	clinical testing	Variant summary: PALB2 c.968C>T (p.Ala323Val) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 250708 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.968C>T has been reported in the literature in at least 1 individual included in a Hereditary Breast And Ovarian Cancer Syndrome case-control study (Weitzel_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. ClinVar contains an entry for this variant (Variation ID: 482023). Based on the evidence outlined above, the variant was classified as uncertain significance.