Submissions for variant NM_024675.4(PALB2):c.3331C>G (p.Pro1111Ala)

gnomAD frequency: 0.00001  dbSNP: rs864622193

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000205952	SCV000259640	uncertain significance	Familial cancer of breast	2025-01-08	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 1111 of the PALB2 protein (p.Pro1111Ala). This variant is not present in population databases (gnomAD no frequency). 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: 219647). 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 tolerated. Experimental studies have shown that this missense change does not substantially affect PALB2 function (PMID: 31757951). 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.
Ambry Genetics	RCV000222857	SCV000273214	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-24	criteria provided, single submitter	clinical testing	The p.P1111A variant (also known as c.3331C>G), located in coding exon 12 of the PALB2 gene, results from a C to G substitution at nucleotide position 3331. The proline at codon 1111 is replaced by alanine, an amino acid with highly similar properties. This alteration was detected in 1/5589 German BRCA1/2-negative probands with breast cancer (Hauke J et al. Cancer Med. 2018 04;7:1349-1358). In one functional study, this variant did not significantly impair homologous recombination efficiency compared to wild-type, and was classified as a variant of uncertain significance by the authors (Boonen RACM et al. Nat Commun. 2019 11;10:5296). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000222857	SCV000686031	uncertain significance	Hereditary cancer-predisposing syndrome	2020-11-08	criteria provided, single submitter	clinical testing	This missense variant replaces proline with alanine at codon 1111 of the PALB2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have shown that this variant resulted in normal repair activity in mouse cells (PMID: 31757951). To our knowledge, this variant has been reported in an individual affected with breast cancer (PMID: 29522266). 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	RCV001800527	SCV000699591	uncertain significance	not specified	2023-06-15	criteria provided, single submitter	clinical testing	Variant summary: PALB2 c.3331C>G (p.Pro1111Ala) results in a non-conservative amino acid change located in the Partner and localiser of BRCA2, 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 was absent in 251456 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3331C>G has been reported in the literature in individuals affected with Breast Cancer (Dorling_2021), however, this report does not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. One publication using mouse embryonic stem cells lacking Palb2 reported that complementation with the human P111A-PALB2 was able to rescue homologous recombination and confer PARPi resistance similar to levels seen with human wildtype-PALB2, with 102.61% and 87.51% relative activity, respectively (Boonen_2019). The following publications have been ascertained in the context of this evaluation (PMID: 31757951, 33471991). Six ClinVar submitters have assessed the variant since 2014: all have classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000587389	SCV002010959	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001800527	SCV002046251	uncertain significance	not specified	2020-09-24	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002478727	SCV002778088	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group N; Pancreatic cancer, susceptibility to, 3	2022-01-11	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000205952	SCV005053865	uncertain significance	Familial cancer of breast	2024-03-15	criteria provided, single submitter	clinical testing
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV004764779	SCV005374657	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-05-14	criteria provided, single submitter	curation	According to the ClinGen ACMG PALB2 v1.0.0 criteria we chose this criterion: BP1 (supporting benign): ClinGen: Apply to all missense variants.
CeGaT Center for Human Genetics Tuebingen	RCV000587389	SCV005433953	likely benign	not provided	2024-11-01	criteria provided, single submitter	clinical testing	PALB2: BP1, BP4, BS3:Supporting