Submissions for variant NM_024675.4(PALB2):c.2615T>C (p.Val872Ala)

dbSNP: rs730881877

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000160828	SCV000211501	uncertain significance	not provided	2024-03-28	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individual(s) with breast cancer (PMID: 28779002); This variant is associated with the following publications: (PMID: 24485656, 19609323, 20871615, 28779002)
Ambry Genetics	RCV000216057	SCV000273450	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-10	criteria provided, single submitter	clinical testing	The p.V872A variant (also known as c.2615T>C), located in coding exon 7 of the PALB2 gene, results from a T to C substitution at nucleotide position 2615. The valine at codon 872 is replaced by alanine, an amino acid with similar properties. This alteration has been reported in at least one subject in a study of 13087 breast cancer cases and 5488 control individuals in the UK (Decker B et al. J Med Genet, 2017 11;54:732-741). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000462998	SCV000550633	uncertain significance	Familial cancer of breast	2024-01-30	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 872 of the PALB2 protein (p.Val872Ala). This variant is present in population databases (rs730881877, gnomAD 0.0009%). 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: 182755). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PALB2 protein function. 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	RCV000216057	SCV001354184	uncertain significance	Hereditary cancer-predisposing syndrome	2022-08-16	criteria provided, single submitter	clinical testing	This missense variant replaces valine with alanine at codon 872 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 one individual affected with breast cancer (PMID: 28779002) and in ClinVar (SCV001551767.1). This variant has been identified in 1/251488 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001420923	SCV001623376	uncertain significance	not specified	2021-04-25	criteria provided, single submitter	clinical testing	Variant summary: PALB2 c.2615T>C (p.Val872Ala) results in a non-conservative amino acid change located in the WD40 domain (IPR031920) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251488 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2615T>C in individuals affected with Breast Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Baylor Genetics	RCV000462998	SCV004202024	uncertain significance	Familial cancer of breast	2023-10-18	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356561	SCV001551767	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The PALB2 p.Val872Ala variant was not identified in the literature nor was it identified in the Cosmic, MutDB, LOVD 3.0, or Zhejiang University databases. The variant was also identified in dbSNP (ID: rs730881877) as "With uncertain significance allele" and ClinVar (classified as uncertain significance by GeneDx, Ambry Genetics, and Invitae). The variant was identified in control databases in 1 of 246264 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European population in 1 of 111716 chromosomes (freq: 0.000009), but not in the other populations. The p.Val872 residue is conserved in mammals but not in more distantly related organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. In addition, the variant occurs outside of the splicing consensus sequence and 3 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume pathogenicity. 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.