Submissions for variant NM_024675.4(PALB2):c.3449T>G (p.Leu1150Arg)

gnomAD frequency: 0.00001  dbSNP: rs45566737

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130657	SCV000185543	uncertain significance	Hereditary cancer-predisposing syndrome	2024-01-16	criteria provided, single submitter	clinical testing	The p.L1150R variant (also known as c.3449T>G), located in coding exon 13 of the PALB2 gene, results from a T to G substitution at nucleotide position 3449. The leucine at codon 1150 is replaced by arginine, an amino acid with dissimilar properties. This alteration has been previously reported in individuals with a personal and/or family history of breast cancer (Rahman N et al. Nat. Genet., 2007 Feb;39:165-7; Thompson ER et al. Breast Cancer Res., 2015 Aug;17:111). In addition, this variant has been reported in individuals diagnosed with colon and/or endometrial cancer (Ring KL et al. Mod. Pathol., 2016 11;29:1381-1389; Pearlman R et al. JAMA Oncol, 2017 Apr;3:464-471). This alteration was also found to be functionally normal in a homology-directed DNA repair (HDR) assay (Wiltshire T et al. Genet Med, 2020 03;22:622-632).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.
Cancer Genetics Laboratory, Peter MacCallum Cancer Centre	RCV000211075	SCV000268030	uncertain significance	Familial cancer of breast	2015-06-01	criteria provided, single submitter	case-control
GeneDx	RCV000588260	SCV000292919	uncertain significance	not provided	2023-07-10	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; Published functional studies demonstrate homology-directed repair comparable to wild-type (Wiltshire et al., 2020); This variant is associated with the following publications: (PMID: 26283626, 27443514, 27978560, 19609323, 20871615, 24485656, 31636395)
Counsyl	RCV000211075	SCV000488473	uncertain significance	Familial cancer of breast	2016-04-07	criteria provided, single submitter	clinical testing
Invitae	RCV000211075	SCV000633435	uncertain significance	Familial cancer of breast	2022-10-14	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1150 of the PALB2 protein (p.Leu1150Arg). This variant is present in population databases (rs45566737, gnomAD 0.007%). This missense change has been observed in individual(s) with breast, endometrial, or colorectal cancer (PMID: 17200668, 26283626, 27443514, 27978560). ClinVar contains an entry for this variant (Variation ID: 141936). 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: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change does not substantially affect PALB2 function (PMID: 31636395). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002281957	SCV000699597	uncertain significance	not specified	2022-07-11	criteria provided, single submitter	clinical testing	Variant summary: PALB2 c.3449T>G (p.Leu1150Arg) 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 1.9e-05 in 257636 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3449T>G has been reported in the literature as a VUS in settings of multigene panel testing among individuals with a variety of cancers such as breast, endometrial and colon (example, Thompson_2015, Rahman_2007, Ring_2016, Pearlman_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function (Wiltshire_2019 cited in Boonen_2019). These results showed no damaging effect of this variant on homology directed repair (HDR). 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.
Color Diagnostics, LLC DBA Color Health	RCV000130657	SCV001358404	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-14	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with arginine at codon 1150 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). A functional study has reported the mutant protein to exhibit normal homology-directed DNA repair function in PALB2-deficient cells (PMID: 31636395). This variant has been reported in two individuals affected with breast cancer (PMID: 17200668, 26283626), one individual with endometrial carcinoma (PMID: 27443514) and two individuals with colorectal cancer (PMID: 27978560). This variant has been identified in 5/251472 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.
Sema4, Sema4	RCV000130657	SCV002531181	uncertain significance	Hereditary cancer-predisposing syndrome	2021-05-20	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000211075	SCV004019647	uncertain significance	Familial cancer of breast	2023-03-31	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Baylor Genetics	RCV000211075	SCV004202008	uncertain significance	Familial cancer of breast	2023-10-22	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000588260	SCV004222343	uncertain significance	not provided	2023-08-18	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in individuals with breast cancer (PMIDs: 26283626 (2015), 17200668 (2007)), endometrial cancer (PMID: 27443514 (2016)), and colorectal cancer (PMID: 27978560 (2017)). Functional evidence reports the variant does not disrupt homology-directed repair (HDR) (PMID: 31636395 (2020)). The frequency of this variant in the general population, 0.000035 (4/113754 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.