Submissions for variant NM_024675.4(PALB2):c.3146T>C (p.Met1049Thr)

gnomAD frequency: 0.00003  dbSNP: rs138273800

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130431	SCV000185295	likely benign	Hereditary cancer-predisposing syndrome	2022-08-08	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Invitae	RCV000204730	SCV000261288	uncertain significance	Familial cancer of breast	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1049 of the PALB2 protein (p.Met1049Thr). This variant is present in population databases (rs138273800, gnomAD 0.004%). This missense change has been observed in individual(s) with breast cancer (PMID: 26283626, 26315354, 26580448). ClinVar contains an entry for this variant (Variation ID: 141785). 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) performed at Invitae indicates that this missense variant is expected to disrupt PALB2 protein function with a positive 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.
Cancer Genetics Laboratory, Peter MacCallum Cancer Centre	RCV000204730	SCV000268024	uncertain significance	Familial cancer of breast	2015-06-01	criteria provided, single submitter	case-control
Color Diagnostics, LLC DBA Color Health	RCV000130431	SCV000292191	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-10	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with threonine at codon 1049 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 each affected with breast cancer (PMID: 26283626), ovarian cancer (PMID: 26315354) and osteosarcoma (PMID: 26580448), respectively. This variant has been detected in a breast cancer case-control meta-analysis in 1/60466 cases and 4/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID PALB2_010778). This variant has been identified in 6/282634 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.
GeneDx	RCV000482622	SCV000567606	uncertain significance	not provided	2023-08-15	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with a personal or family history of osteosarcoma, breast, or ovarian cancer (Ramus et al., 2015; Thompson et al., 2015; Zhang et al., 2015); This variant is associated with the following publications: (PMID: 26580448, 26283626, 26315354, 19609323, 24485656, 20871615)
Counsyl	RCV000204730	SCV000785635	uncertain significance	Familial cancer of breast	2017-10-17	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000482622	SCV000888371	uncertain significance	not provided	2021-05-24	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001194140	SCV001363439	uncertain significance	not specified	2019-06-06	criteria provided, single submitter	clinical testing	Variant summary: PALB2 c.3146T>C (p.Met1049Thr) 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 2e-05 in 251228 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3146T>C has been reported in the literature in individuals affected with Breast Cancer and Epithelial Ovarian cancer (Thompson_2015, Ramus_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary forms of Breast and Ovarian Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven 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.
Genetic Services Laboratory, University of Chicago	RCV001194140	SCV002066174	uncertain significance	not specified	2019-06-28	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002505109	SCV002814826	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group N; Pancreatic cancer, susceptibility to, 3	2022-05-13	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000204730	SCV004019674	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].
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003389456	SCV004101679	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 5	2023-11-13	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1049 of the PALB2 protein (p.Met1049Thr).This amino acid position is conservative (PhyloP=5.26). This variant is present in population databases (rs138273800, gnomAD 0.004%). This missense change has been observed in individual(s) with breast cancer (PMID: 26283626, 26315354, 26580448,19609323, 24485656, 20871615). ClinVar contains an entry for this variant (Variation ID: 141785). In silico analysis supports that this missense variant has a deleterious effect on protein structure/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.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV003444205	SCV004171513	uncertain significance	Fanconi anemia complementation group N	2023-10-25	criteria provided, single submitter	clinical testing	The PALB2 c.3146T>C (p.Met1049Thr) missense change has a maximum subpopulation frequency of 0.0056% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. This variant is absent in a database of women older than 70 years of age who have never had cancer (FLOSSIES, https://whi.color.com/). This variant has been reported in individuals with a personal and/or family history of breast cancer (PMID: 26283626, 32885271) and ovarian cancer (PMID: 26315354). To our knowledge, this variant has not been reported in individuals with Fanconi anemia. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
Baylor Genetics	RCV000204730	SCV004202016	uncertain significance	Familial cancer of breast	2023-10-20	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004544294	SCV004763413	uncertain significance	PALB2-related disorder	2024-01-16	criteria provided, single submitter	clinical testing	The PALB2 c.3146T>C variant is predicted to result in the amino acid substitution p.Met1049Thr. This variant has been reported in individuals with osteosarcoma, breast, or ovarian cancer (Table S4, Ramus et al. 2015. PubMed ID: 26315354; Table 3, Thompson et al. 2015. PubMed ID: 26283626; Table S4a, Zang et al. 2015. PubMed ID: 26580448). This variant is reported in 0.0056% of alleles in individuals of Latino descent in gnomAD. It is interpreted as uncertain significance by the vast majority of submitters in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/141785/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355887	SCV001550901	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The PALB2 p.Met1049Thr variant was not identified in the literature nor was it identified in the Cosmic, LOVD 3.0, Zhejiang Colon Cancer Database, databases. The variant was identified in dbSNP (ID: rs138273800) as With Uncertain significance allele, ClinVar (classified as uncertain significance by Ambry Genetics, Invitae, Color Genomics, GeneDx), Clinvitae (classified as uncertain significance by ClinVar, Invitae), MutDB, databases. The variant was identified in control databases in 5 of 277046 chromosomes at a frequency of 0.000018 (Genome Aggregation Consortium Feb 27, 2017). Although the p.Met1049 residue is not conserved in mammals and other organisms, computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. The variant is located within the ‘WD40-repeat-containing domain’ functional domain increasing the likelihood that it may have clinical significance. 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.