Submissions for variant NM_024675.4(PALB2):c.571C>G (p.Pro191Ala)

dbSNP: rs587780221

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000116110	SCV000150019	uncertain significance	not provided	2013-11-05	criteria provided, single submitter	clinical testing	This variant is denoted PALB2 c.571C>G at the cDNA level, p.Pro191Ala (P191A) at the protein level, and results in the change of a Proline to an Alanine (CCA>GCA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. PALB2 Pro191Ala 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. This variant is a conservative substitution of one neutral non-polar amino acid for another, altering a position that is only moderately conserved throughout evolution and is not located in a known functional domain. In silico analyses predict this variant to have a benign effect on protein structure and function. Based on the currently available information, we consider PALB2 Pro191Ala to be a variant of uncertain significance.
Cancer Genetics Laboratory, Peter MacCallum Cancer Centre	RCV000211086	SCV000267988	uncertain significance	Familial cancer of breast	2015-06-01	criteria provided, single submitter	case-control
Color Diagnostics, LLC DBA Color Health	RCV000774642	SCV000908508	uncertain significance	Hereditary cancer-predisposing syndrome	2021-03-17	criteria provided, single submitter	clinical testing	This missense variant replaces proline with alanine at codon 191 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 individuals affected with breast cancer (PMID: 26283626, 28779002). 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.
Invitae	RCV000211086	SCV001205830	uncertain significance	Familial cancer of breast	2022-03-19	criteria provided, single submitter	clinical testing	Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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. ClinVar contains an entry for this variant (Variation ID: 128146). This variant has not been reported in the literature in individuals affected with PALB2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 191 of the PALB2 protein (p.Pro191Ala).
Ambry Genetics	RCV000774642	SCV003867649	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-10	criteria provided, single submitter	clinical testing	The p.P191A variant (also known as c.571C>G), located in coding exon 4 of the PALB2 gene, results from a C to G substitution at nucleotide position 571. The proline at codon 191 is replaced by alanine, an amino acid with highly similar properties. This alteration was identified in 0/1996 high risk breast cancer patients and 1/1998 unaffected controls (Thompson ER et al. Breast Cancer Res. 2015 Aug;17:111). In another study this alteration was been reported in 1/13087 breast cancer cases and 0/5488 control individuals in the UK (Decker B et al. J Med Genet. 2017 11;54:732-741). This amino acid position is 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.