Submissions for variant NM_024675.4(PALB2):c.2897T>C (p.Ile966Thr)

gnomAD frequency: 0.00003  dbSNP: rs587780214

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212819	SCV000150003	uncertain significance	not provided	2024-03-27	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies are inconclusive: partially reduced homologous repair activity compared to wild type (PMID: 31757951); Observed in individuals with personal or family history of breast and other cancers, including one individual who was also reported to harbor an MLH1 pathogenic variant, as well as unaffected controls (PMID: 35263119, 25575445, 26328243, 33471991, 35534704, 35610400); This variant is associated with the following publications: (PMID: 25575445, 26328243, 24485656, 19609323, 20871615, 33471991, 35263119, 35610400, 35534704, 31757951)
Ambry Genetics	RCV000116094	SCV000216349	uncertain significance	Hereditary cancer-predisposing syndrome	2022-06-01	criteria provided, single submitter	clinical testing	The p.I966T variant (also known as c.2897T>C), located in coding exon 9 of the PALB2 gene, results from a T to C substitution at nucleotide position 2897. The isoleucine at codon 966 is replaced by threonine, an amino acid with similar properties. This alteration was reported in an individual with triple negative breast cancer diagnosed at age 51, contralateral breast cancer and endometrial cancer at age 63, and colorectal cancer at age 68. This individual was also found to have a pathogenic MLH1 mutation (Ollier M et al. Am J Cancer Res 2015; 5(7):2113-26). This alteration was also reported in 1/1250 families who were tested clinically for hereditary breast cancer and had previously tested negative for BRCA1 and BRCA2 mutations (Nguyen-Dumont T et al. Breast Cancer Res. Treat. 2015 Jan; 149(2):547-54). Additionally, one functional study found that this alteration did not demonstrate a significant reduction in homologous recombination efficiency or a significant reduction in resistance to PARP inhibitor compared to wildtype (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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000204848	SCV000261308	uncertain significance	Familial cancer of breast	2024-01-04	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 966 of the PALB2 protein (p.Ile966Thr). This variant is present in population databases (rs587780214, gnomAD 0.007%). This missense change has been observed in individual(s) with a personal and/or family history of breast and/or ovarian cancer (PMID: 25575445, 26328243, 35610400). ClinVar contains an entry for this variant (Variation ID: 128136). 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. 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.
Color Diagnostics, LLC DBA Color Health	RCV000116094	SCV000685988	likely benign	Hereditary cancer-predisposing syndrome	2021-05-21	criteria provided, single submitter	clinical testing
Counsyl	RCV000204848	SCV000784956	uncertain significance	Familial cancer of breast	2017-02-17	criteria provided, single submitter	clinical testing
Mendelics	RCV000116094	SCV000839010	uncertain significance	Hereditary cancer-predisposing syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212819	SCV000889590	uncertain significance	not provided	2017-12-26	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000764045	SCV000894999	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group N; Pancreatic cancer, susceptibility to, 3	2018-10-31	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000212819	SCV001245835	uncertain significance	not provided	2020-01-01	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000116094	SCV002530735	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-02	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002267857	SCV002551644	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002267857	SCV002571877	uncertain significance	not specified	2022-08-08	criteria provided, single submitter	clinical testing	Variant summary: PALB2 c.2897T>C (p.Ile966Thr) 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 allele was found at a frequency of 3.6e-05 in 251462 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2897T>C has been reported in the literature in individuals with a personal and/or family history of breast cancer and other cancers, including one case where it was observed with a pathogenic variant in MLH1 (e.g. Nguyen-Dumont_2015, Ollier_2015, Dorling_2021, Delahunty_2022). These report(s) do not provide unequivocal conclusions about association of the variant with Breast Cancer. An experimental study found that the variant protein had only a mildly reduced homologous recombination efficiency compared to the wild-type protein, suggesting the variant has little impact on protein function (e.g. Boonan_2019). Thirteen submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and the majority classified it as VUS (n=12), with one classifying the variant as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
Myriad Genetics, Inc.	RCV000204848	SCV004019691	likely benign	Familial cancer of breast	2023-03-31	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
Baylor Genetics	RCV000204848	SCV004202076	uncertain significance	Familial cancer of breast	2024-03-14	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV004760383	SCV005368773	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 5	2024-10-09	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 966 of the PALB2 protein (p.Ile966Thr). This variant is present in population databases (rs587780214, gnomAD 0.007%). This amino acid position is highly conserved ( PhyloP=5.18) . This missense change has been observed in individual(s) with a personal and/or family history of breast and/or ovarian cancer (PMID: 25575445, 26328243, 35610400). ClinVar contains an entry for this variant (Variation ID: 128136). In addition, the in silico prediction for this alteration is inconclusive. 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. Pathogenic/likely pathogenic mutations in the PALB2 gene cause susceptibility to breast cancer (OMIM# 114480).
Molecular Oncology Laboratory, Centre Jean Perrin	RCV000202384	SCV000257398	association	Triple-negative breast cancer	2015-02-26	no assertion criteria provided	case-control	PALB2 protein absent in tumor tissue (IHC)
Leiden Open Variation Database	RCV000212819	SCV001193311	uncertain significance	not provided	2019-12-04	no assertion criteria provided	curation	Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Andreas Laner.