chr16-23630344-G-A
Variant summary
Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2
The NM_024675.4(PALB2):c.1810C>T(p.Leu604Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000309 in 1,614,164 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Consequence
NM_024675.4 synonymous
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -16 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00186 AC: 283AN: 152194Hom.: 2 Cov.: 32
GnomAD3 exomes AF: 0.000406 AC: 102AN: 251376Hom.: 0 AF XY: 0.000250 AC XY: 34AN XY: 135872
GnomAD4 exome AF: 0.000148 AC: 216AN: 1461852Hom.: 1 Cov.: 33 AF XY: 0.000116 AC XY: 84AN XY: 727218
GnomAD4 genome AF: 0.00186 AC: 283AN: 152312Hom.: 2 Cov.: 32 AF XY: 0.00172 AC XY: 128AN XY: 74480
ClinVar
Submissions by phenotype
not provided Benign:4
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PALB2: BP1, BP4, BS2 -
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not specified Benign:3
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. -
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Hereditary cancer-predisposing syndrome Benign:3
This alteration is classified as 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. -
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Familial cancer of breast Benign:2
Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Marc Tischkowitz. -
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Breast and/or ovarian cancer Benign:1
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Familial ovarian cancer Benign:1
The PALB2 p.Leu604= variant was identified in 1 of 558 proband chromosomes (frequency: 0.002) from individuals or families with breast cancer and was not identified in 520 control chromosomes from healthy individuals (Zheng 2012). The variant was also identified in the following databases: dbSNP (ID: rs144015319) as "With other allele", ClinVar (classified as benign by Invitae, GeneDx, Color Genomics; as likely benign by Ambry Genetics and Quest Diagnostics Nichols Institute San Juan Capistrano), Clinvitae, and in LOVD 3.0 (1x probably does not affect function). The variant was not identified in Cosmic, or Zhejiang University databases. The variant was identified in control databases in 151 of 277136 chromosomes at a frequency of 0.001 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 145 of 24032 chromosomes (freq: 0.01), Latino in 5 of 34418 chromosomes (freq: 0.0002), European in 1 of 126630 chromosomes (freq: 0.00001); it was not observed in the “Other”, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Leu604= 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, HumanSpliceFinder) 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. -
Hereditary breast ovarian cancer syndrome Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at