ClinVar Miner

Submissions for variant NM_024675.4(PALB2):c.2067G>A (p.Ser689=)

gnomAD frequency: 0.00004  dbSNP: rs371149159
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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000165391 SCV000216118 likely benign Hereditary cancer-predisposing syndrome 2014-08-26 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: 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 RCV000197495 SCV000252858 benign Familial cancer of breast 2021-12-15 criteria provided, single submitter clinical testing
Cancer Genetics Laboratory,Peter MacCallum Cancer Centre RCV000197495 SCV000268045 likely benign Familial cancer of breast 2015-06-01 criteria provided, single submitter case-control
GeneDx RCV000420216 SCV000518126 likely benign not specified 2017-06-15 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Color Diagnostics, LLC DBA Color Health RCV000165391 SCV000685915 likely benign Hereditary cancer-predisposing syndrome 2016-10-11 criteria provided, single submitter clinical testing
Counsyl RCV000197495 SCV000785070 likely benign Familial cancer of breast 2017-04-04 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000420216 SCV000919943 benign not specified 2018-04-23 criteria provided, single submitter clinical testing Variant summary: PALB2 c.2067G>A alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant was observed with an allele frequency of 3.2e-05 in 246256 control chromosomes (gnomAD). The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 2-folds higher than the estimated maximal expected allele frequency for a pathogenic variant in PALB2 causing Hereditary Breast and Ovarian Cancer phenotype (0.00016), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. The variant, c.2067G>A, has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Phuah_2013, Thompson_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Multiple ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as "likely benign/benign." Based on the evidence outlined above, the variant was classified as benign.
Illumina Laboratory Services,Illumina RCV001119747 SCV001278186 uncertain significance Fanconi anemia complementation group N 2017-09-11 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV001284030 SCV001469591 likely benign not provided 2019-09-30 criteria provided, single submitter clinical testing
Genetic Services Laboratory,University of Chicago RCV000420216 SCV002068911 likely benign not specified 2021-07-29 criteria provided, single submitter clinical testing
Sema4,Sema4 RCV000165391 SCV002530665 likely benign Hereditary cancer-predisposing syndrome 2022-02-02 criteria provided, single submitter curation
Leiden Open Variation Database RCV000197495 SCV001193180 likely benign Familial cancer of breast 2019-05-13 no assertion criteria provided curation Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitters to LOVD: Marc Tischkowitz, Yukihide Momozawa.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001356268 SCV001551388 likely benign Carcinoma of colon no assertion criteria provided clinical testing The PALB2 p.Ser689= variant was identified in 14 of 16340 proband chromosomes (frequency: 0.0009) from individuals or families with breast cancer and was present in 36 of 22482 control chromosomes (frequency: 0.002) from healthy individuals (Momozawa 2018, Phuah 2013, Thompson 2015). The variant was also identified in dbSNP (ID: rs371149159) as "With Likely benign, other allele", ClinVar (classified as benign by Invitae; as likely benign by Ambry Genetics, GeneDx, and three other submitters), and in LOVD 3.0 (4X). The variant was identified in control databases in 8 of 246256 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 1 of 111712 chromosomes (freq: 0.000009), East Asian in 6 of 17248 chromosomes (freq: 0.0004), and South Asian in 1 of 30782 chromosomes (freq: 0.00003); it was not observed in the African, Other, Latino, Ashkenazi Jewish, and Finnish, populations. The p.Ser689= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.

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